1. Introduction

Alcoholic beverages have been consumed for recreational purposes in most parts of the world since before recorded history began. According to the latest World Health Organization (WHO) global estimates (WHO, 2021), about 5.1% of the global adult population is living with alcohol use disorders (AUD). Another study by the global burden of disease (GBD) collaborative network reported a 1.5% global AUD prevalence in 2019, highlighting variabilities between countries (Castaldelli-Maia and Bhugra, 2022). Ethanol, the main active component of alcoholic beverages, is currently one of the most used psychoactive drugs on the market. Ethanol produces a state of anxiolysis and disinhibition, which is commonly sought after in social situations or in individuals with AUD (Gilman et al., 2008). Alcohol consumption is also causally related to the development of approximately 230 diseases or disorders, including infectious diseases, malignant neoplasms, cardiovascular system due to ethanol’s effect on blood pressure and inflammation (Chiva-Blanch and Badimon, 2019), mental and behavioral disorders, neurological diseases, digestive diseases, and injuries (Rehm et al., 2017). While consumption patterns vary, the impact of ethanol at low doses on overall health remains unclear (Larsson et al., 2020; Zhao et al., 2023). A recent systematic meta-analysis of cohort studies showed no statistically significant protective effect of alcohol on all-cause mortality at low ethanol intakes (Zhao et al., 2023). Studies have highlighted that abstinence from alcohol has many health benefits, including improved sleep. On the contrary, the risk of certain types of cancer, heart disease, and stroke increases with increased alcohol consumption (Savin et al., 2018; Paradis et al., 2022), and chronic consumption of ethanol in high doses is also linked to feelings of dysphoria, cognitive deficits, and an increased risk of developing AUD (Trantham-Davidson and Chandler, 2015).

Two major diagnostic classification systems are used to define AUD. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), developed by the American Psychiatric Association, defines AUD as a cluster of behavioral and physical symptoms, including withdrawal, tolerance, and craving (American Psychological Association, 2013). The International Classification of Diseases 11^th Revision (ICD-11), developed by the World Health Organization, divides AUD into a harmful pattern of alcohol use and alcohol dependence. Alcohol dependence is characterized by “a strong internal drive to use alcohol, which is manifested by an impaired ability to control use, increasing priority given to use over other activities, and persistence of use despite harm or negative consequences” (WHO-ICD11, 2022). According to the ICD-10 definition of AUD, it was estimated that in 2016, approximately 8.6% of adult men and 1.7% of adult women suffered from AUD globally (Carvalho et al., 2019).

AUD may be characterized by the development of tolerance due to homeostatic adaptation in the brain compulsive seeking and withdrawal upon cessation of consumption (Liang and Olsen, 2014). AUD symptomatology includes a wide range of behaviors such as poor control over drinking and impulsivity (a failure to inhibit excessive drive), reward deficiency (a reduced response to natural rewards), maladaptive learning (the growing incentive salience of a drug’s predictive cues with chronic use), the emergence of opponent processes (the power of negative motivational states underlying withdrawal), faulty decision making (inaccurate computation in preparation for action) or automaticity of responses (inflexibility of stimulus–response habits) (Volkow et al., 2013). Due to neuronal dependency on alcohol for regular activity in individuals with AUD, cessation of alcohol consumption often leads to withdrawal (Littleton, 1998). Sudden cessation might result in acute withdrawal symptoms, including delirium, seizures, and cognitive dysfunctions (Jesse et al., 2017; Laniepce et al., 2020). However, the symptoms seen in alcohol withdrawal range in severity depending on the volume and duration of ethanol consumption and inter-individual variability (Newman et al., 2023). Withdrawal symptoms are often related to hyperexcitability, such as insomnia, anxiety, palpitations, agitation, and even seizures (Saunders et al., 2019), likely related to alteration in the functioning of the brain inhibition system.

Due to its hydrophilic nature, ethanol readily penetrates all biological membranes and crosses the blood–brain barrier. Once in the organism, ethanol metabolism happens in the liver but also in the brain due to the presence of alcohol dehydrogenase (ADH), catalase, and P450 (CYP2E1) in both organs. Such metabolism routes produce mainly three metabolites: acetaldehyde, salsolinol, and acetate (Gil-Mohapel et al., 2019; Wilson and Matschinsky, 2020). After reaching the brain, ethanol and its metabolites induce diverse disturbances such as reduced glucose uptake, increased monocarboxylate uptake, dopaminergic, GABAergic, and glutamatergic alterations (Peana et al., 2017).

Since, ethanol and its metabolites act on multiple biological pathways of the central nervous system (CNS), therapeutic interventions relying on various approaches have been developed with variable degrees of efficacy. However, there is still a significant need to understand better the underlying mechanism leading to AUD and associated symptoms and develop more efficient intervention strategies. While impacting many CNS pathways, one of the main pathways altered by alcohol is the inhibitory pathway utilizing gamma-aminobutyric acid (GABA).

This review provides an overview of the impact of ethanol on brain functions related to GABA, describes existing therapeutic interventions, lists their shortcomings, and summarizes the existing knowledge around GABAergic functions in AUD involved in the expression of symptoms and outcomes before providing insight into the development of future therapeutic interventions acting on the GABAergic system.

2. Impact of ethanol on brain

Ethanol produces a wide variety of behavioral and physiological effects in the body, but exactly how it acts to produce these effects is still poorly understood. Like most dependence-producing substances, ethanol binds and acts on multiple proteins, receptors, and signaling pathways throughout the brain (Figure 1A), including amino acids, opioids, enzymes, and ion channels (Heinz et al., 2009; Koob and Volkow, 2016). The primary targets behind ethanol-induced behavioral phenotypes (disinhibition, hyperlocomotion, and anxiolysis) are GABA_A receptors. Besides modulating GABA_A receptor activity, ethanol can directly bind and modulate the activity of several proteins, including ionotropic glutamatergic (NMDA) receptors, alcohol dehydrogenase (ADH), and glycine receptors (Grant and Lovinger, 2018). Further, it has been observed that ethanol is capable of indirect modulation of other neurotransmitters (dopamine, serotonin, opioid, and cholinergic), particularly in brain regions involved in the mesolimbic reward system [i.e., amygdala, hippocampus, striatum, and ventral tegmental area (VTA)] via GABAergic/glutamatergic neurons or their respective receptors present on other types of neurons (Abrahao et al., 2017). Therefore, chronic ethanol consumption in large volumes drives a chemical imbalance in the brain and forces a homeostatic response to maintain neurochemical equilibrium and functionality (De Witte, 2004). As the brain chemically adapts to excess ethanol, it forms a new equilibrium in which ethanol becomes integral in neuronal function (Figure 1B; Valenzuela, 1997; Pérez-Ramírez et al., 2022). In individuals with AUD, this is manifested through increased tolerance to the effects of ethanol, which can lead to the consumption of alcohol near toxicity levels to experience the effects of alcohol, such as relaxation, anxiolysis, or disinhibition. Consistent with this notion, magnetic resonance spectroscopy (MRS) studies generally demonstrate lower cortical GABA levels in individuals with AUD, specifically during withdrawal, than in control participants (Prisciandaro et al., 2019; Kirkland et al., 2022; Shyu et al., 2022).

Therefore, the main activity of ethanol is thought to be on glutamatergic and GABAergic signaling pathways, with an increase or decrease of function depending on the state (acute consumption, chronic consumption, or withdrawal), inducing a cascade of events acting on dopamine, serotonin, and endogenous opioid release (Ferraguti et al., 2015).

2.1. Impact of ethanol on glutamate and GABA

Preclinical and clinical studies showed that ethanol binds to and inhibits the functions of the glutamatergic receptors (NMDA, AMPA, Kainate, and mGluR5) (Möykkynen and Korpi, 2012; Ferraguti et al., 2015). It also binds to and facilitates the functions of the GABA_A and GABA_B receptors (Valenzuela and Jotty, 2015; Olsen and Liang, 2017), which, combined with the effect of glutamatergic receptors, causes an overall imbalance in neuronal activity, thought to be responsible for “blackout” moments after acute heavy drinking (Wetherill and Fromme, 2016; Yang et al., 2022) and contributing to excitotoxicity and loss of synaptic plasticity (Chandrasekar, 2013). Data from studies using human transcranial magnetic stimulation (TMS), a non-invasive neuromodulation approach that probes GABA-receptor-mediated cortical inhibition, confirmed that alcohol intake increases GABA-inhibitory neurotransmission and decreases NMDA-receptor-activated excitatory neurotransmission (Ziemann et al., 2015). Interestingly, the activity of ethanol metabolites on glutamatergic and GABAergic targets seems different, which could explain the dynamic changes happening during drinking episodes (see Section 2.6 below).

Preclinical studies in rats have also confirmed the critical impact of ethanol on the regulation of ethanol-maintained responses through GABA_A receptor-dependent signaling in the central nucleus of the amygdala (Avegno et al., 2018; Barchiesi et al., 2021; Kisby et al., 2021). Preclinical studies have also confirmed the impact of alcohol on behavioral outcomes [compulsive behavior (Giuliano et al., 2018), withdrawal-induced hyperalgesia (Avegno et al., 2018), increased anxiety (Barchiesi et al., 2021), altered cognitive functions], and biological pathways [GABA and glutamine (McCunn et al., 2022), glutamate (Vengeliene et al., 2005; Mira et al., 2019), dopamine (Ma and Zhu, 2014; Solanki et al., 2020)] as well as provided insights onto therapeutic interventions (Foo et al., 2019).

2.2. Impact of ethanol on acetylcholine

Ethanol intake in rats was also shown to bind to the nicotinic-subtype receptor of acetylcholine (Davis and de Fiebre, 2006) and to increase acetylcholine levels in the VTA (Larsson et al., 2005), facilitating the influx of dopamine onto the nucleus accumbens (NAc). Such activity in the VTA and NAc is thought to contribute to positive reinforcement of alcohol. In contrast, modulation of the nicotinic receptors of the hippocampus and amygdala is thought to be involved in negative effects (Tarren et al., 2016). Ethanol’s binding and activity at nicotinic receptors are also thought to interfere with nicotine-induced desensitization, which could explain the high prevalence of co-use of alcohol and tobacco (Davis and de Fiebre, 2006; Addolorato et al., 2012).

2.3. Impact of ethanol on dopamine

As a downstream effect of alcohol consumption, ethanol induces an indirect increase in dopamine release and acetylcholine activity from the VTA to the NAc, a brain region strongly associated with reward and motivation (Boehm II et al., 2004). Preclinical Studies have also shown that dopamine is released in the ventral striatum and NAc, contributing to drug reward, which could be further increased by nicotine co-administration (Tizabi et al., 2007). The activation of central GABAergic neurotransmission, particularly through GABA_B receptors, is also linked to the mesolimbic dopaminergic neurotransmission during rewarding processes, altogether contributing to the addictive properties of ethanol (Addolorato et al., 2012).

2.4. Impact of ethanol on serotonin

Acute alcohol consumption increases serotonin release, contributing to the rewarding aspect of consuming alcohol (Banerjee, 2014). Previous studies showed that acute ethanol augments the firing rate of the serotoninergic 5-HT₃ receptors, and longer consumption can affect the expression and function of various other subtypes, including 5-HT₂, without a clear understanding of whether it is a direct effect or mediated by a cascade of events or adaptation (Lovinger, 1997).

2.5. Impact of ethanol on opioids

Consumption of alcoholic beverages has also been shown to increase the levels of endogenous opioids (Mitchell et al., 2012), which are subsequently drastically reduced during withdrawal, leading to craving and increasing the risk of opioid-seeking behaviors (Turton et al., 2020). The activity of ethanol at GABA_A receptors in the VTA and NAc facilitates endogenous opioid release in the VTA, contributing to the alcohol-induced feeling of euphoria (Colasanti et al., 2012). Opioid-targeting treatments such as naltrexone or nalmefene diminish these effects of alcohol (Turton et al., 2020), providing further evidence of the impact of alcohol on the opioid system.

2.6. Impact of ethanol metabolism on various neurotransmitters

Acetaldehyde, salsolinol, and acetate, metabolites of ethanol, seem to participate in the effect of alcohol, but their contribution is less understood. Acetaldehyde in the brain causes euphoria at low doses and plays a vital role in ethanol’s reinforcing properties, thereby facilitating alcohol addiction (Quertemont et al., 2005; Peana et al., 2017). One of the primary studies reported that acetaldehyde increased GABA uptake but did not affect both its release and synthesis (Bobrova and Covaltchuk, 1980). Acetaldehyde has been shown to stimulate dopaminergic neurons (Melis et al., 2007) and μ opioid receptors (Sanchez-Catalan et al., 2014). Acetaldehyde is a highly reactive and short-lived metabolite of ethanol that reacts with biogenic amines like dopamine and forms condensation products like Salsolinol.

Studies reported that salsolinol may exert some of the effects of ethanol by activating μ opioid receptors on GABAergic neurons signaling onto dopaminergic neurons in the mesolimbic system. However, the mechanisms are complex, and it seems like salsolinol would reduce GABAergic activity while ethanol increases it, suggesting opposite responses on GABAergic receptor activity from ethanol and one of its metabolites, also causing a downstream opposite effect on dopamine release (Peana et al., 2017).

Finally, the direct role of acetate on GABAergic regulation has not been reported. However, acetate was reported to contribute to increased cerebral blood flow (Tanabe et al., 2019), increased neuronal excitability, and enhanced glutamatergic activity (Chapp et al., 2021), whereas ethanol boosts GABA-mediated inhibition. Accordingly, existing literature indicates that concrete experimental evidence is required to confirm the effects of ethanol’s metabolites on the GABAergic system.

3. GABAergic mechanisms involved in AUD

GABA is the main inhibitory neurotransmitter in the brain. It exerts its function by binding to two types of receptors: GABA_A and GABA_B. GABA_A receptors are ionotropic chloride channels (Enna, 2007), while GABA_B are metabotropic G-coupled protein receptors (GPCR) (Pinard et al., 2010). GABA_B receptors mediate slow inhibitory transmission, while GABA_A mediates fast inhibition. GABA_A and GABA_Bhave been extensively reviewed for their potential in pharmacotherapies (Sarasa et al., 2020) and link to AUD (Ghit et al., 2021; Holtyn and Weerts, 2022).

GABA_A receptors are heteropentamers composed of various subunits such as α, β, γ, δ, ε, θ, π, and ρ (Figures 2A,B), which are found throughout the brain (Fritschy and Mohler, 1995), including regions involved in alcohol-related use such as the prefrontal cortex, thalamus, cerebellum, or the amygdala (Bowery et al., 1987). Ethanol acts as a positive allosteric modulator (PAM) of GABA_A receptors, binding to several subunits, mostly α-subunits, thus explaining its sedative and neuromodulating properties (Ghit et al., 2021). Other PAMs include benzodiazepines and Z-drugs that promote sedation, anxiolysis, muscle relaxation, and anti-seizure properties.

GABA_B receptors are the only metabotropic G protein-coupled receptors for GABA (Figure 2C) and can be found in presynaptic (auto-inhibitory) and postsynaptic membranes and distributed throughout the CNS and PNS. The two main subunits of the GABA_B receptor are GABA_BR1 and GABA_BR2. For the GABA_B receptors to be active and functional, these subunits need to interact to form a stable heterodimer. Importantly, orthosteric agonists and antagonists bind to GABA_BR1, while PAMs bind to the GABA_BR2 subunit. GABA_B receptors are primarily found in the cerebellum, prefrontal cortex, and thalamus, in addition to the interpeduncular nucleus and the olfactory nucleus (Bowery et al., 1987). Alcohol is known to interact with the GABA_Breceptors in the brain, but the exact binding site and mechanism of action are not completely understood. GABA_B receptor-binding drugs have anti-convulsant and analgesic properties (Terunuma, 2018) and are also found to reduce craving and withdrawal symptoms in dependent individuals [for example, Baclofen (Logge et al., 2022)].

4. From alcohol use to alcohol use disorders – the GABAergic system

DSM-5 classifies substance-related disorders into substance-use disorders (SUD) and substance-induced disorders (intoxication, withdrawal, and other substance/medication-induced mental ailments). Clinically, SUDs occur in a range of severity based on a number of symptom criteria endorsed. Mild (2–3 symptoms), moderate (4–5), and severe (>5). The DSM-5 diagnostic criteria do not describe levels or types of alcohol use or alcohol use harms (American Psychological Association, 2013); however, for this review, we chose to include some of the most commonly used categories of this kind (e.g., binge alcohol use) for a better illustration of the AUD pathophysiology and the involvement of GABAergic system to align with clinical presentations of AUD and alcohol withdrawal. AUD encompasses various disorders characterized by different consumption patterns, impacting the brain and the GABAergic system. Alcohol consumption, including alcohol use not meeting the criteria for AUD, also impacts the GABAergic system. For example, minimal alcohol intake will enter the brain and target GABA_A receptors, causing a cascade of regulatory events, potentially leading to behavioral changes. When consumption becomes chronic, or during binge drinking episodes, the impact of alcohol on the brain is even more profound, triggering activation/inhibition of other biological pathways (as described earlier in Figure 1). Table 1 below summarizes alcohol use at different levels, explains the different considerations given for men and women, and highlights the impact on the GABAergic system and symptoms related to the use of alcohol.

4.1. Occasional, moderate, and safe use of alcohol with low risk for AUD

The safe or moderate use of alcohol is considered with less than 2 drinks per day for men and 1 for women (0.02–0.04 g/dL blood alcohol concentration), where the risk for developing AUD remains low. Even with such use, the acute or low level of ethanol present in the system is enough to potentiate the action of GABA at GABA_Areceptors, inducing relaxation. Even in rats, acute ethanol administration induces a state of anxiolysis driven by the potentiation of the GABA_A receptor in the basolateral amygdala, acting on multiple cell populations (Herman and Roberto, 2016). Low levels of ethanol already play a role in the expression and trafficking of GABA_Areceptors in the brain by rapidly downregulating α₄β₃δ-GABA_A receptors in the hippocampus (Chandler et al., 2017). Expression of the α₁β₃γ₂-GABA_A receptors is also downregulated after several hours of consumption, followed by an upregulation of α₄β₃γ₂ and α₂β₃γ₁ after a couple of days. This demonstrates the broad and long-lasting kinetics of an acute consumption of ethanol, which is reversible, but the recovery timeline is dose-dependent (Holford, 1987).

During medium-risk drinking, i.e., drinking episodes of alcohol when the volume of alcohol is consumed in a short period but not binge drinking (not more than 5 drinks in 2 h for men, 4 in 2 h for women, and < 0.08 g/dL) (World Health Organization, 2000), ethanol levels can range from 5 to 30 mmol/L. This potentiates the GABA_Areceptors in the brain, decreasing excitatory glutamatergic neurotransmission and causing slight sedation, a feeling of relief, slight alteration of short-term memory, decreased attention, and potential mood changes (Liang and Olsen, 2014). Studies in rats have demonstrated that this dose level increases GABAergic firing rate and afferent-evoked synaptic response in the VTA, a central hub for dopaminergic projections in the brain, regulating motivation, cognition, reward valuation, and addiction. This impact on the VTA, potentially driven by changes in firing rates from the GABAergic system, contributes to increased alcohol intake (Tateno and Robinson, 2011).

Interestingly, preclinical studies using rats also demonstrated that reducing α₄-subunit expression via a viral-mediated RNA interfering with the α₄-protein synthesis in the NAc allowed for a reduction of self-administered ethanol. Similar results were observed when pharmacologically blocking the GABA_A receptors in the paraventricular nucleus of the hypothalamus, further confirming the role of GABAergic potentiation in increasing alcohol intake and seeking behaviors (Li et al., 2011).

4.2. At-risk drinking patterns

Greater than the threshold set for safe and moderate use described above, consumption of alcohol is considered at risk (NIAAA, 2018). In this case, ethanol induces GABA_A receptor activation in the VTA, NAc, hypothalamus, and hippocampus, causing an overall imbalance in excitation/inhibition, leaning toward increased inhibition. At a certain point, thought to be above 13 mmol/L (Liang and Olsen, 2014), the reward pathways of the mesolimbic system are directly and indirectly activated (as described in the previous section on Impact of Ethanol on the Brain), allowing dopamine release, which fosters the development of addictive properties of alcohol consumption.

4.3. Alcohol use disorder

AUD is considered when the drinking pattern is above established standards, either due to volume or frequency of intake. One tool used worldwide to identify AUD is the Alcohol Use Disorder Identification Tool (AUDIT), developed by WHO (Higgins-Biddle and Babor, 2018). While the classification of AUD has changed over the years and is country-dependent, most medical and addiction professionals frequently break AUD into two categories: binge and heavy drinking (Kranzler and Soyka, 2018).

Binge drinking is the acute consumption of large amounts of alcohol (for example, five or more drinks in less than 2 h for men and four or more for women, leading to >0.08 g/dL of blood alcohol concentration). Binge drinking leads to cognitive deficits, reduced inhibition, and reduced ability to control alcohol intake voluntarily, thereby increasing the chances of developing more frequent AUD in the future (Chmielewski et al., 2020). Risk factors for binge drinking include age, male sex, alcohol consumption at a young age, a patient’s state of mental health, and genetic susceptibility (NIAAA, 2020).

Preclinical studies of psychological changes and alcohol consumption have determined that in young rats (postnatal days 28–42), binge drinking induces a state of anxiety-like behavior and leads to alcohol dependence in adulthood (Pandey et al., 2015). Stress and withdrawal-induced anxiety are correlated to increased voluntary ethanol drinking in alcohol-preferring rats (Meyer et al., 2013), and chronic psychosocial stressed male mice showed increased voluntary ethanol drinking (Bahi, 2013). Human magnetic resonance spectroscopy studies have shown that cortical GABA levels are reduced in young adult binge drinkers (Marinkovic et al., 2022). Following acute high-dose ethanol administration in rats, thalamic α₄-GABA_Areceptor levels were regulated temporally, as a decrease was observed at 2 h followed by a delayed transient increase (Werner et al., 2016). Other studies using a transgenic dopaminergic D3 receptor knockout mouse model combined with an α6-GABA_A receptor ligand (RO 15–4,513) also showed that increased GABAergic inhibition in the NAc contributes to reducing binge drinking, confirming the critical role of GABAergic neurotransmission in reducing alcohol intake (Leggio et al., 2019).

Heavy drinking is defined as drinking more than recommended during a week, leading to 0.1–0.2 g/dL of blood alcohol concentration, depending on the number of drinks. For a man, having more than 15 standard alcoholic drinks weekly is considered heavy drinking. For women, having more than 8 drinks a week meets the criteria for heavy drinking (NIAAA, 2018). Heavy drinking leads to increased neuronal atrophy and reduces white matter fiber integrity (Daviet et al., 2022), associated with increased risk for dependence, anxiety, depression, cognitive deficits, altered control over drinking habits, cardiovascular diseases, and other health risks.

Studies have shown that the behavioral changes are primarily due to the plastic changes of GABA_A receptors that occur after chronic ethanol exposure, which include significantly reduced post-synaptic α₁ and increased α₄-containing GABA_A receptors. The subunit composition of GABA_A receptor subtypes is expected to determine their physiological properties and pharmacological profiles. An in-depth study of GABA_A-subunits using genetically engineered mice has shown that the α₁ subunit involves sedation, anti-convulsant activity, anterograde amnesia functions, etc., while the α₄subunit is involved in changes in mood and anxiety. Thus, these GABA_A receptor subunit composition changes are a mechanism underlying the behavioral changes after chronic ethanol exposure, which leads to additional risks of developing dependence. Heavy drinking triggered by chronic stress and any induced anxiety is an additional risk factor for developing alcohol dependence, observed in animal models and humans (McCaul et al., 2017). Conversely, stopping or reducing alcohol consumption, in turn, aggravates stress or anxiety due to an overall imbalance in brain homeostasis (Schmidt et al., 2016).

4.4. Chronic/daily alcohol use leading to dependence

With chronic alcohol consumption comes an increased risk for reward-associated habitual alcohol abuse, pronounced craving behavior for alcohol, and inability to stop seeking alcohol. This is usually highly linked to the development of dependence, a severe form of AUD that occurs when a person develops tolerance to the effect of alcohol and, therefore, seeks further alcohol consumption to prevent experiencing withdrawal symptoms. Alcohol dependence is a serious condition that requires comprehensive treatment to address the physical, emotional, and behavioral aspects of AUD.

Postmortem studies found a loss of GABAergic markers in the human brains of adults with alcohol dependence, particularly in men (Behar et al., 1999; Dodd et al., 2006). Transcranial magnetic stimulation (TMS) studies also demonstrated that chronic alcohol dependence has some level of impact on GABA_A and GABA_B receptor function, which seems to vary from study to study (Mohammadi et al., 2006; Ziemann et al., 2015). Several studies found no effects on short-interval cortical inhibition or TMS-evoked N45 potential (Conte et al., 2008; Nardone et al., 2010; Mon et al., 2012; Naim-Feil et al., 2016), thought to index GABA_A receptor function. However, other studies found a general decrease in GABA levels (Prisciandaro et al., 2019; Shyu et al., 2022), including in youth with alcohol dependence (Kaarre et al., 2018). Given the dynamic nature of alcohol’s effects on GABA, the GABA levels depend on several states (e.g., recently detoxified or more prolonged abstinence) and traits (e.g., age). One report on long-interval cortical inhibition thought to index GABA_B showed decreases in alcohol-dependent patients (Naim-Feil et al., 2016).

Multiple preclinical studies demonstrated that chronic ethanol consumption alters GABA_A receptor plasticity, leading to ethanol dependence (Olsen and Liang, 2017). Other preclinical studies established that general GABA_A receptor expression and function changes in cases of alcohol dependence, both synaptically and extra-synaptically, in brain regions highly involved in establishing dependence and symptom emergence (i.e., the cortex, hippocampus, and central amygdala). This translates into a general loss of phasic and tonic GABAergic inhibition, tolerance to ethanol, and cross-tolerance to benzodiazepines and other sedative-hypnotics acting on GABA receptors (Kumar et al., 2009; Olsen and Liang, 2017; Bohnsack et al., 2018).

With such alteration in overall GABAergic functioning, a drastic imbalance in excitation/inhibition develops across multiple brain regions [medial prefrontal cortex (Pleil et al., 2015)], amygdala circuit (Herman et al., 2016; Herman and Roberto, 2016; Hughes et al., 2019), intrahippocampal circuits (Liang et al., 2004), and VTA circuits (Arora et al., 2013) causing a decrease in inhibitory control in multiple neurotransmitter firing activity, leading to the emergence of various behavioral changes including cognitive deficits, seeking behavior, humor changes, and others (Morrow et al., 2020).

Chronic alcohol consumption in heavy drinking, dependence, and associated GABA_Aplasticity changes also lead to DA release changes in the reward neurocircuitry. During acute alcohol withdrawal, changes occur, such as upregulation of α₄-containing GABA_A receptors and downregulation of α₁- and α₃-containing GABA_Areceptors (Liang and Olsen, 2014). GABA_A receptor downregulation may contribute to anxiety and seizures of withdrawal. During withdrawal periods, rats show a significant decrease in DA and serotonin levels in the reward neurocircuitry commonly associated with dysphoria, depression, and anxiety disorders. These psychological changes may also contribute to ethanol-seeking behavior, again demonstrating the complexity of changes induced by chronic alcohol consumption.

5. Existing interventions

Existing therapeutic interventions for AUD and alcohol withdrawal have attempted to harness the various CNS systems on which alcohol acts to limit the harms associated with alcohol consumption. The existing therapeutic interventions have diverse efficacy levels, various side effects, and contraindications (Table 2). Several clinical trials have shown the efficacy of certain pharmacotherapies that are approved by regulatory agencies for treating AUD or withdrawal and that are used off-label (Carpenter et al., 2018; Sloan et al., 2020).

5.1. Non-GABAergic pharmacologic interventions

Disulfiram has been an FDA-approved drug used to treat AUD since 1951. It inhibits the acetaldehyde dehydrogenase enzyme involved in ethanol metabolism, leading to higher plasma concentrations of acetaldehyde, which induces unpleasant side effects if a patient consumes alcohol while taking this medication, preventing further drinking. Disulfiram-induced reactions can include hepatotoxicity and death, which is why disulfiram needs to be used with caution (Kranzler and Soyka, 2018; Stokes and Abdijadid, 2022). Nowadays, the most used pharmacotherapy is naltrexone (commercialized under the brand name Revia®), a competitive μ opioid receptor antagonist and a partial antagonist of the δ and κ opioid receptors (Liang and Olsen, 2014; Sloan et al., 2020; Singh and Saadabadi, 2023). It decreases craving by reducing the rewarding and euphoric effects of alcohol and is one of the few AUD pharmacotherapies approved by the FDA. It is generally well tolerated but has minor side effects (Singh and Saadabadi, 2023).

Acamprosate is an FDA-approved drug used in Europe and North America for alcohol craving and relapse prevention (Franck and Jayaram-Lindström, 2013; Kalk and Lingford-Hughes, 2014). Although its exact mechanisms are unknown, it decreases glutamate during alcohol withdrawal through NMDA receptor modulation and indirectly potentiates GABA_A receptors. Acamprosate is generally well tolerated (Kalk and Lingford-Hughes, 2014).

Nalmefene is another antagonist of the μ and δ opioid receptors but is a partial agonist at the κ receptor. It is currently approved for AUD indication in Australia and Europe. Nalmefene decreases dopamine release in the NAc and reduces alcohol dependence and consumption by decreasing the rewarding and craving effects of alcohol (Paille and Martini, 2014). It can help control alcohol intake and has shown better results in those benefiting from psychosocial support. It has mild side effects, which generally disappear with time (Paille and Martini, 2014; López-Pelayo et al., 2020).

5.2. GABAergic pharmacologic interventions

Baclofen is only approved for the treatment of alcohol withdrawal in France (Garbutt, 2019). Despite multiple trials supporting its efficacy in reducing the risk of relapse and increasing abstinence days (Agabio et al., 2023), its efficacy remains controversial, and systematic reviews consider the evidence of its efficacy insufficient (Jonas et al., 2014). It acts as an agonist at the GABA_B receptor and decreases dopamine release in the mesolimbic system, which reduces craving and withdrawal symptoms in dependent individuals. Baclofen has multiple side effects, limiting its use (Romito et al., 2021).

Gabapentin is a GABA analog used as an anti-epileptic medication for over 30 years. Clinical trials have shown dose-dependent efficacy in reducing craving, reducing anxiety, and facilitating abstinence (Anton et al., 2020). However, some studies also raise concerns due to its sedating properties and documentation of extra-medical use of this medication (Modesto-Lowe et al., 2019; Weresch et al., 2021). It was also found that Gabapentin causes respiratory depression when used alone and increases the risk of opioid-related deaths when combined with opioids (Gomes et al., 2017). Despite being a GABA analog, its mechanism of action is still unclear and seems unrelated to GABAergic modulation. Its main target seems to be the α₂δ-subunit of the voltage-gated calcium channel. It also increases GABA concentrations in the brain (Cai et al., 2012).

Topiramate is not yet approved by the FDA for the treatment of AUD. Still, clinical trials have demonstrated reductions in craving and risk of relapse and increasing abstinence (Kranzler et al., 2014; Manhapra et al., 2019; Wetherill et al., 2021). It is an approved anti-convulsant for treating epilepsy and seems to act through GABA_Areceptor modulation (Fariba and Saadabadi, 2022). It also binds the AMPA receptor to decrease glutamate release and decreases dopamine release in the NAc. It has some side effects, including paresthesia, dysgeusia, anorexia, and cognitive impacts such as slowing mental and physical activity and trouble concentrating or attention (Wenzel et al., 2006).

Benzodiazepines (BZ) are allosteric modulators of the GABA_A receptor that bind to the α_{1, 2, 3, 5,} and γ subunits. They enhance the activity of GABA when binding at its receptor and are recommended in managing acute alcohol withdrawal (Nelson et al., 2019), but not for the treatment of AUD itself. They can lead to sedation, ataxia, anterograde amnesia, and have abuse potential (Engin, 2022). Alcohol delays the metabolism of BZ (Hoyumpa, 1984), prolonging its bioavailability, causing psychomotor impairment, and increasing the risk of overdosing of BZ. Studies showed that BZ also modulates part of ethanol’s reinforcing and/or aversive properties. BZ and ethanol co-consumption is also known to amplify the effect of alcohol.

5.3. Psychotherapeutic interventions

In contrast to pharmacological interventions, Cognitive Behavioral Therapy (CBT) is a form of psychotherapy that involves challenging automatic thoughts, cognitive distortions, existing beliefs, and problematic behaviors (Chand et al., 2023). It is one of the most studied forms of treatment for SUD and has the most support from evidence-based studies. Adults with problematic drinking who received CBT showed decreased alcohol consumption, and newer variants of CBT, such as virtual reality-assisted CBT (Thaysen-Petersen et al., 2023), appear to be more successful than traditional methods (Carroll and Kiluk, 2017).

Motivational Enhancement Therapy (MET) is another psychosocial treatment that applies principles from motivational psychology. MET is often the foundation of brief interventions for risky alcohol use, and indeed, protocols can be very short, requiring only a few sessions of client-centered interventions (Ceci et al., 2022). MET focuses on identifying a reason for a change in alcohol consumption, but outcomes vary substantially with commitment and readiness to change to have an impact (Hodgins et al., 2009).

However, existing therapeutic options have shown limitations. Some drugs, repurposed from other indications, show direct or indirect activity in the GABAergic system (Gabapentin, topiramate, and baclofen). The GABAergic system is a key player in the pathophysiology of AUD and alcohol withdrawal and is a desirable target for drug development (Liang and Olsen, 2014; Mirijello et al., 2015). Indeed, the previous sections showed how intertwined central pathways are in the context of ethanol consumption and how instrumental the GABAergic system is in modulating most of the effects, directly or indirectly. However, AUD is broad and can vary in expression in multiple ways (volume consumed, acute or chronic consumption, etc.). Therefore, the impact of ethanol on the GABAergic system may vary depending on the manifestation of AUD, and different interventions acting on different aspects of the GABAergic system may be required to elicit optimal outcomes in treating AUD or alcohol withdrawal. The following sections will present novel GABAergic interventions currently being investigated.

6. GABAergic interventions in preclinical models and their impact on alcohol-related symptoms: reconciling risk and benefits

6.1. GABA_A: involvement in AUD and therapeutic potential

Since ethanol facilitates the activity of GABA and has such a large effect on GABAergic receptor expression and function, it can be difficult to anticipate what impact a GABAergic drug would have on individuals with AUDs. Benzodiazepines (BZ), binding at the interface between α_1-2-3-5 and γ subunits of the GABA_A receptors, are known enhancers of phasic GABAergic inhibition across brain regions and induce internalization of synaptic GABA_A receptors (Gallager et al., 1984; Tehrani and Barnes, 1997). Therefore, BZs promote the mechanisms leading to some ethanol-induced deficits in GABAergic inhibition. However, BZs have beneficial effects in the context of acute withdrawal symptoms as they act as a substitute for ethanol and can help individuals in withdrawal re-establish a new excitation/inhibition balance without alcohol (refer to Figure 1B).

In recent years, BZ-derivatives acting preferentially at selected α-subunits were developed and tested in preclinical models for their activity on ethanol self-administration and craving behaviors (Table 3). Activation of α₂/α₃-GABA_A receptors by the HZ-166, XHe-II-053, YT-III-31, or YT-III-271 PAMs in ethanol discrimination studies augmented the reinforcing effects of ethanol via increasing the self-administration in rhesus monkeys (Berro et al., 2019). These findings are aligned with clinical evidence that demonstrated a positive association of both the GABRA2 and GABRA3 gene expression with an increased risk for developing alcoholism (Covault et al., 2004; Enoch, 2008; Soyka et al., 2008; Mallard et al., 2018). Similarly, potentiation of the α₅-GABA_A receptor via QH-ii-066 administration was also shown to enhance the reinforcing effects of alcohol in non-human primates, while using an inverse agonist at the α₅-GABA_A receptor (Xli-093) inhibited such reinforcement effects (Rüedi-Bettschen et al., 2013). Consistently, intra-hippocampal infusions of an α₅-GABA_A receptor inverse agonist RY023 reduced ethanol-maintained responses in a dose-dependent manner, suggesting that the α₅-GABA_Areceptors in the hippocampus play an important role in regulating ethanol-seeking behaviors (June et al., 2001). This was further supported by studies using the partial α₅-GABA_A receptor inverse agonist Ro 15–4,513, by the selective α₅₋GABA_A inverse agonist (α5IA-II) (Stephens et al., 2005) and by the use of the α₅-GABA_A receptor knockout mice model showing reduced ethanol preference (Boehm II et al., 2004; Stephens et al., 2005).

However, the studies mentioned above all evaluated the impact of positive modulation of the α_x-GABA_A receptor in the context of alcohol consumption or alcohol discrimination when the system is already sensitized to further GABAergic activity (Figure 1B – central panel). However, it remains unclear how such modulation would play in the context of withdrawal when the system is deficient in GABAergic regulation, which is, in turn, causing craving behaviors. Knowing the anti-craving effect of BZ (Nelson et al., 2019), one could expect that the α₂-, α₃- or α₅-PAMs can contribute to the anti-craving effect of BZ in a brain system during a withdrawal state and could further elicit beneficial effects without the side effects observed with benzodiazepines.

While BZ and derivatives bind and act at the interface between α_1-2-3-5 and γ subunits, neurosteroids bind between α and β subunits of the GABA_A receptors. Furthermore, such binding is greatly facilitated by the presence of the δ subunit in the pentamer (Gatta et al., 2022; Figure 2B). Neurosteroids are potent and effective neuromodulators synthesized from cholesterol in glial and neuronal cells of the central (CNS) and peripheral nervous systems (PNS). They act at extrasynaptic receptors, facilitating tonic inhibition (Chen et al., 2019; Belelli et al., 2022). With acute alcohol intake, the cerebral levels of allopregnanolone were found to be increased, whereas its levels were reduced during chronic alcohol consumption and withdrawal (Romeo et al., 1996). In addition, stimulation of neurosteroidogenesis by metyrapone was found to reduce cocaine intake in rats (Goeders and Guerin, 2008), and one could suppose a similar effect for alcohol intake.

Recent studies found that allopregnanolone has antidepressant properties for women with postpartum depression (Pinna et al., 2022), a disorder with reduced GABAergic function (Prevot and Sibille, 2021). Therefore, with their action of the GABAergic system, and their involvement in arousal, cognition, emotion, and motivation, neurosteroids may hold therapeutic potential in treating AUD (Zorumski et al., 2013; Gatta et al., 2022), and such effects are being investigated (Morrow et al., 2020; Mounier et al., 2021).

6.2. GABA_B: involvement in AUD and therapeutic potential

The involvement of GABA_B receptors in the development of AUD is still unclear. However, studies in clinical populations (using Baclofen) and animals [experimental candidates listed in Table 4 (Maccioni and Colombo, 2019)] showed that GABA_Breceptor modulation was beneficial in AUD management. For instance, rats receiving baclofen showed reduced hyper-locomotion caused by acute alcohol administration (Besheer et al., 2004), and reduced anxiety-like behavior and tremors following chronic alcohol withdrawal (Knapp et al., 2007). Table 4 includes a list of GABA_BPAMs such as CGP7930, GS39783, BHF177, Rac-BHFF, ADX71441, CMPPE, COR659, and ORM-27669 that were primarily studied in rodent models and were found to be beneficial in AUDs.

7. Novel therapeutic agents targeting the GABAergic system in clinical trials

7.1. Pharmacological interventions

With the increased characterization of the impact of alcohol on the GABAergic system and the increasing characterization of the link between GABAergic functions, receptor subtype, and symptom relief in the context of AUD, more clinical trials are being initiated to investigate how GABAergic modulation can contribute to better treatment of AUDs and alcohol withdrawal (Table 5). Interventions acting on GABA_A receptors are investigated in multiple clinical trials. For example, DZ is already the standard of care for reducing withdrawal symptoms. Midazolam, another benzodiazepine, and propofol, a GABA_A receptor agonist, were withdrawn from Phase 4 studies in 2016 due to logistical reasons. They were studied for their potential effect on stress response and immune functions in mechanically ventilated patients with AUDs.

Brexanolone, a GABA_A-targeting neurosteroid, is about to start recruiting for a Phase 1 study to demonstrate safety before assessing efficacy in participants with AUD and PTSD. Brexanolone is already approved for treating postpartum depression (Morrow et al., 2020).

Baclofen, a GABA_B agonist, is currently under Phase 4 to assess its efficacy in managing acute alcohol withdrawal. As mentioned in Table 1, baclofen is already approved in France for reducing craving and withdrawal syndrome, but some literature suggests its efficacy for this indication is limited (Cooney et al., 2019). ASP8062, a GABA_B-PAM, is currently investigating the efficacy of 2 weeks of treatment in a Phase 2 study in participants with moderate AUD at reducing alcohol cravings. Preclinical studies in rats showed promising effects in reducing alcohol self-administration without side effects observed with baclofen (Haile et al., 2021), and phase 1 studies in humans confirmed the safety of ASP8062 (Ito et al., 2022).

The antiepileptic valproate also acts indirectly on the GABAergic system by blocking the metabolism of GABA and by blocking GABA reuptake, increasing GABA levels in the brain (Janmohamed et al., 2020). Clinical trials are ongoing to determine the efficacy of valproate treatment at reducing ethanol withdrawal, compared to benzodiazepines, here lorazepam. Lorazepam was also used in another open-label clinical trial completed in 2013 to assess the efficacy of a combination with disulfiram. Reports showed a significant reduction in anxiety, depression, and craving; such effects were observed 24 weeks after intervention (Bogenschutz et al., 2016).

7.2. Non-pharmacological interventions – rTMS

Repetitive transcranial magnetic stimulation, i.e., rTMS, is a noninvasive neurostimulation modality delivering focused magnetic field pulses to the cortex that modulate cortical activity. Treatment sessions are generally delivered daily over several weeks, which results in the induction of long-term changes in cortical excitability through neuroplasticity. This includes modulation of the implicated neurocircuits underlying alcohol use disorder and is under investigation as a potential treatment. Enduring changes in cortical activity (namely inhibition and excitation) resulting from rTMS have implications for enduring changes in GABA activity (Daskalakis et al., 2006). Over a decade ago, the first published clinical trial demonstrated efficacy in reducing cravings in adults with AUD over a sham-control condition (Mishra et al., 2010). Since then, the majority of trials have delivered rTMS over the left or right dorsolateral prefrontal cortex, with a recent meta-analysis showing a signal for reduced alcohol craving with rTMS treatment (Sorkhou et al., 2022), potentially driven by the impact of rTMS on GABAergic signaling. However, most RCTs have been small single-center trials, and given the substantial heterogeneity in parameters utilized across studies, the optimal protocol has not yet been determined.

Additionally, there is growing interest in using deep rTMS™ using coils (H Coils) that can induce a broader electrical field within the cortex. For example, a recent RCT using rTMS with an H7 Coil stimulating the bilateral medial prefrontal cortex and anterior cingulate cortex showed positive results in reducing craving and alcohol consumption in treatment-seeking patients with AUD (Harel et al., 2022). Moreover, another trial that utilized a coil that stimulates the bilateral lateral PFC and insula showed efficacy for nicotine dependence in a large, definitive, multi-site RCT that subsequently paved the way for FDA clearance for this indication (Zangen et al., 2021), demonstrating the first time FDA cleared indication for any substance use disorder. Taken together, further exploration of the therapeutic potential of rTMS for AUD is warranted. Given the well-described link between GABA dysfunction in AUD and rTMS effects on the GABAergic system, it will be important to explore whether biomarkers of GABAergic functions can serve as mediators or moderators of rTMS efficacy.

8. Conclusion

Alcohol use-related disorders are significant risk factors for other high mortality-causing diseases. Although the mechanisms are elusive, the GABAergic system’s involvement seems critical in AUD development. Currently, GABAergic drugs are used in the second or third line of treatment of AUD and mitigation of alcohol withdrawal. Studies indicate that pharmacological modulation of GABA receptors may be a promising therapeutic option in achieving long-term abstinence by decreasing the daily alcohol intake and withdrawal effects. However, extensive research is needed in this line to uncover the pharmacological potential of the GABAergic system in managing alcohol use-related disorders.

GABAergic Signaling in Alcohol Use Disorder and Withdrawal: Pathological Involvement and Therapeutic Potential

1. Introduction

Alcoholic beverages have been consumed for recreation globally for centuries. Recent estimates indicate that between 1.5% and 5.1% of the worldwide adult population experiences alcohol use disorders (AUD). Ethanol, the primary active component in alcoholic beverages, is a widely used psychoactive substance known to induce states of anxiety reduction and disinhibition, often sought in social settings or by individuals with AUD. However, alcohol consumption is also linked to approximately 230 diseases, including various infectious diseases, cancers, cardiovascular issues, mental health conditions, neurological disorders, and injuries. While the impact of low-dose ethanol on overall health remains under investigation, recent analyses suggest no statistically significant protective effect on all-cause mortality, and abstinence from alcohol is associated with numerous health benefits. Conversely, increased alcohol consumption elevates the risk of certain cancers, heart disease, and stroke, with chronic high-dose intake also contributing to dysphoria, cognitive deficits, and a higher risk of developing AUD.

AUD is defined by major diagnostic systems such as the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which describes it as a spectrum of behavioral and physical symptoms, including withdrawal, tolerance, and craving. The International Classification of Diseases 11th Revision (ICD-11) categorizes AUD into harmful alcohol use and alcohol dependence, characterized by a powerful internal drive to consume alcohol, impaired control, prioritization of alcohol over other activities, and continued use despite negative consequences. Globally, a significant portion of the adult population, particularly men, is affected by AUD.

The progression of AUD often involves the development of tolerance, where the brain adapts to alcohol's presence, and compulsive seeking and withdrawal symptoms upon cessation. Symptoms of AUD can encompass poor drinking control, impulsivity, reduced response to natural rewards, maladaptive learning, negative emotional states during withdrawal, impaired decision-making, and automatic responses. Due to the brain's reliance on alcohol for regular function in individuals with AUD, stopping consumption frequently leads to withdrawal. Abrupt cessation can result in severe acute withdrawal symptoms like delirium, seizures, and cognitive dysfunction. The severity of these symptoms varies based on the volume and duration of ethanol consumption, as well as individual differences, often manifesting as hyperexcitability symptoms such as insomnia, anxiety, palpitations, agitation, and seizures, likely stemming from disruptions in the brain's inhibitory system.

Ethanol's hydrophilic nature allows it to easily penetrate biological membranes and cross the blood-brain barrier. Within the body, ethanol is metabolized in the liver and brain, producing metabolites such as acetaldehyde, salsolinol, and acetate. Once in the brain, ethanol and its metabolites cause various disturbances, including reduced glucose uptake, altered monocarboxylate uptake, and disruptions in dopaminergic, gamma-aminobutyric acid (GABAergic), and glutamatergic systems. Given ethanol's impact on multiple central nervous system (CNS) pathways, various therapeutic interventions have been developed with varying success. However, a deeper understanding of the mechanisms underlying AUD and its symptoms is still needed to develop more effective strategies. Among the many CNS pathways affected by alcohol, the inhibitory pathway involving GABA is significantly altered. This discussion aims to provide an overview of ethanol's impact on brain functions related to GABA, describe existing therapeutic interventions and their limitations, and summarize current knowledge regarding GABAergic functions in AUD, offering insights for future therapeutic developments.

2. Impact of Ethanol on Brain

Ethanol elicits a broad range of behavioral and physiological effects, though its precise mechanisms remain under investigation. Similar to most substances causing dependence, ethanol interacts with multiple proteins, receptors, and signaling pathways throughout the brain, including those involving amino acids, opioids, enzymes, and ion channels. The primary targets responsible for ethanol-induced behaviors such as disinhibition, increased movement, and anxiety reduction are GABAA receptors. Beyond modulating GABAA receptor activity, ethanol can directly bind to and influence the function of other proteins, including ionotropic glutamatergic (NMDA) receptors, alcohol dehydrogenase (ADH), and glycine receptors. Furthermore, ethanol has been observed to indirectly modulate other neurotransmitters, such as dopamine, serotonin, opioids, and acetylcholine, particularly within brain regions of the mesolimbic reward system, including the amygdala, hippocampus, striatum, and ventral tegmental area (VTA).

Consequently, chronic high-volume ethanol consumption creates a chemical imbalance in the brain, prompting a homeostatic response to maintain neurochemical equilibrium and functionality. As the brain chemically adapts to excessive ethanol, a new equilibrium is established where ethanol becomes essential for neuronal function. In individuals with AUD, this adaptation is manifested as increased tolerance to ethanol's effects, potentially leading to consumption levels near toxicity to achieve desired effects like relaxation, anxiety reduction, or disinhibition. Consistent with this, magnetic resonance spectroscopy (MRS) studies often show lower cortical GABA levels in individuals with AUD, especially during withdrawal, compared to control participants. Therefore, ethanol's primary action is thought to involve glutamatergic and GABAergic signaling pathways, with effects varying based on the consumption state (acute, chronic, or withdrawal), initiating a cascade of events affecting dopamine, serotonin, and endogenous opioid release.

Preclinical and clinical studies demonstrate that ethanol binds to and inhibits glutamatergic receptors (NMDA, AMPA, Kainate, and mGluR5), while simultaneously binding to and facilitating the function of GABAA and GABAB receptors. This combined effect, along with the impact on glutamatergic receptors, contributes to an overall imbalance in neuronal activity, believed to be responsible for alcohol-induced "blackout" periods following heavy drinking, and contributing to excitotoxicity and loss of synaptic plasticity. Human transcranial magnetic stimulation (TMS) studies confirm that alcohol intake enhances GABA-inhibitory neurotransmission and reduces NMDA-receptor-activated excitatory neurotransmission. Interestingly, the activity of ethanol metabolites on glutamatergic and GABAergic targets appears to differ, which may explain the dynamic changes observed during drinking episodes. For instance, preclinical rat studies confirm ethanol's significant impact on GABAA receptor-dependent signaling in the central nucleus of the amygdala, influencing ethanol-maintained responses. These studies also support alcohol's influence on behavioral outcomes like compulsive behavior, withdrawal-induced hyperalgesia, increased anxiety, and altered cognitive functions, as well as biological pathways involving GABA, glutamine, glutamate, and dopamine, offering insights into therapeutic interventions.

Ethanol intake in rats has also been shown to bind to the nicotinic-subtype acetylcholine receptor and increase acetylcholine levels in the VTA, thereby facilitating dopamine influx into the nucleus accumbens (NAc). This activity in the VTA and NAc is believed to contribute to alcohol's positive reinforcement. Conversely, modulation of nicotinic receptors in the hippocampus and amygdala is thought to be involved in negative effects. Ethanol's interaction with nicotinic receptors may also interfere with nicotine-induced desensitization, potentially explaining the high prevalence of co-use of alcohol and tobacco. As a downstream effect of alcohol consumption, ethanol indirectly increases dopamine release and acetylcholine activity from the VTA to the NAc, a brain region strongly associated with reward and motivation. Preclinical studies also indicate dopamine release in the ventral striatum and NAc contributes to drug reward, potentially amplified by nicotine co-administration. Activation of central GABAergic neurotransmission, particularly through GABAB receptors, is also linked to mesolimbic dopaminergic neurotransmission during rewarding processes, collectively contributing to ethanol's addictive properties. Acute alcohol consumption increases serotonin release, contributing to the rewarding aspects of alcohol. Previous research suggests acute ethanol enhances the firing rate of serotoninergic 5-HT3 receptors, while prolonged consumption can affect the expression and function of other subtypes, like 5-HT2, though the exact mechanisms (direct effect versus cascade) are not fully understood.

Alcoholic beverage consumption also elevates endogenous opioid levels, which significantly decrease during withdrawal, leading to craving and an increased risk of opioid-seeking behaviors. Ethanol's activity at GABAA receptors in the VTA and NAc facilitates endogenous opioid release in the VTA, contributing to the euphoria associated with alcohol. Opioid-targeting treatments, such as naltrexone or nalmefene, reduce these alcohol effects, further supporting alcohol's impact on the opioid system.

Ethanol's metabolites—acetaldehyde, salsolinol, and acetate—also contribute to alcohol's effects, although their precise roles are less understood. Acetaldehyde, at low doses in the brain, induces euphoria and plays a crucial role in ethanol's reinforcing properties, thereby facilitating alcohol addiction. It has been shown to increase GABA uptake and stimulate dopaminergic neurons and μ opioid receptors. Acetaldehyde is a highly reactive, short-lived metabolite that forms condensation products like salsolinol with biogenic amines such as dopamine. Studies suggest salsolinol may mimic some ethanol effects by activating μ opioid receptors on GABAergic neurons that signal dopaminergic neurons in the mesolimbic system. However, the mechanisms are complex, as salsolinol appears to reduce GABAergic activity while ethanol increases it, suggesting opposing effects on GABAergic receptor activity from ethanol and one of its metabolites, leading to a downstream opposite effect on dopamine release. The direct role of acetate on GABAergic regulation has not been widely reported, though it contributes to increased cerebral blood flow, enhanced neuronal excitability, and glutamatergic activity, contrasting with ethanol's promotion of GABA-mediated inhibition. Therefore, further experimental evidence is needed to fully clarify the effects of ethanol's metabolites on the GABAergic system.

3. GABAergic Mechanisms Involved in AUD

GABA serves as the primary inhibitory neurotransmitter in the brain, exerting its effects by binding to two main receptor types: GABAA and GABAB. GABAA receptors are ionotropic chloride channels, responsible for fast inhibitory transmission, while GABAB receptors are metabotropic G-protein-coupled receptors (GPCRs), mediating slower inhibitory transmission. Both GABAA and GABAB receptors have been extensively studied for their therapeutic potential in pharmacotherapies and their links to AUD.

GABAA receptors are heteropentamers composed of various subunits (e.g., α, β, γ, δ, ε, θ, π, and ρ), distributed throughout the brain in regions critical for alcohol-related behaviors, such as the prefrontal cortex, thalamus, cerebellum, and amygdala. Ethanol acts as a positive allosteric modulator (PAM) of GABAA receptors, binding to several subunits, predominantly α-subunits, which accounts for its sedative and neuromodulating properties. Other PAMs, including benzodiazepines and Z-drugs, also enhance GABAA receptor activity, promoting sedation, anxiety reduction, muscle relaxation, and anti-seizure effects.

GABAB receptors are the sole metabotropic G-protein-coupled receptors for GABA, found in both presynaptic (auto-inhibitory) and postsynaptic membranes throughout the central and peripheral nervous systems. These receptors require the interaction of two main subunits, GABABR1 and GABABR2, to form a stable, functional heterodimer. Orthosteric agonists and antagonists bind to GABABR1, while PAMs bind to the GABABR2 subunit. GABAB receptors are primarily located in the cerebellum, prefrontal cortex, thalamus, interpeduncular nucleus, and olfactory nucleus. Alcohol is known to interact with GABAB receptors in the brain, though the precise binding site and mechanism of action are not fully understood. GABAB receptor-binding drugs exhibit anti-convulsant and analgesic properties and have been shown to reduce craving and withdrawal symptoms in dependent individuals, as exemplified by Baclofen.

4. From Alcohol Use to Alcohol Use Disorders – the GABAergic System

The DSM-5 classifies substance-related disorders into substance-use disorders (SUD) and substance-induced disorders (e.g., intoxication, withdrawal). SUD severity is categorized based on the number of symptoms endorsed: mild (2–3 symptoms), moderate (4–5), and severe (>5). While the DSM-5 criteria do not explicitly define levels of alcohol use or harm, commonly used categories like binge alcohol use are included here to better illustrate AUD pathophysiology and the GABAergic system's involvement in clinical presentations. AUD encompasses various disorders characterized by different consumption patterns, each impacting the brain and the GABAergic system. Even minimal alcohol intake affects the GABAergic system, with the acute presence of ethanol sufficient to potentiate GABAA receptors, inducing relaxation and initiating a cascade of regulatory events that can lead to behavioral changes. As consumption becomes chronic or during binge drinking episodes, alcohol's impact on the brain intensifies, activating or inhibiting other biological pathways. The effects of alcohol on the GABAergic system and associated symptoms vary significantly with the pattern of alcohol use.

Even at low-risk consumption levels, such as less than two drinks per day for men and one for women, acute or low levels of ethanol potentiate GABAA receptors, leading to relaxation. Preclinical studies in rats demonstrate that acute ethanol administration induces anxiety-reducing effects by potentiating GABAA receptors in the basolateral amygdala, affecting multiple cell populations. Low ethanol levels rapidly downregulate α4β3δ-GABAA receptors in the hippocampus, and α1β3γ2-GABAA receptors are also downregulated after several hours, followed by upregulation of α4β3γ2 and α2β3γ1 subunits after a few days. This illustrates the broad and prolonged kinetics of acute ethanol consumption, which are reversible, with recovery time being dose-dependent. During medium-risk drinking, where alcohol is consumed rapidly but not at binge levels, ethanol concentrations can range from 5 to 30 mmol/L. This level potentiates GABAA receptors, reducing excitatory glutamatergic neurotransmission and causing mild sedation, feelings of relief, slight short-term memory impairment, decreased attention, and potential mood changes. Studies in rats indicate this dose increases GABAergic firing rates and synaptic responses in the VTA, a key hub for dopaminergic projections involved in motivation, cognition, reward valuation, and addiction, thereby contributing to increased alcohol intake. Preclinical studies also show that reducing α4-subunit expression or pharmacologically blocking GABAA receptors in specific brain regions can decrease self-administered ethanol, confirming the role of GABAergic potentiation in increased alcohol intake and seeking behaviors.

Consumption exceeding established safe and moderate thresholds is considered "at-risk drinking." At these levels, ethanol activates GABAA receptors in the VTA, NAc, hypothalamus, and hippocampus, resulting in an overall imbalance favoring increased inhibition. Beyond a certain threshold, thought to be above 13 mmol/L, the mesolimbic reward pathways are directly and indirectly activated, releasing dopamine, which fosters the development of alcohol's addictive properties. Alcohol use disorder (AUD) is diagnosed when drinking patterns consistently exceed recommended standards in terms of volume or frequency, often identified using tools like the Alcohol Use Disorder Identification Tool (AUDIT). Clinically, AUD is frequently categorized into binge and heavy drinking. Binge drinking, defined as acute consumption of large amounts of alcohol (e.g., five or more drinks for men, four or more for women, within two hours, leading to >0.08 g/dL blood alcohol concentration), results in cognitive deficits, reduced inhibition, and impaired voluntary control over intake, increasing the likelihood of future AUD development. Risk factors include age, male sex, early alcohol consumption, mental health status, and genetic susceptibility. Preclinical studies show that binge drinking in young rats induces anxiety-like behavior and alcohol dependence in adulthood, and stress- or withdrawal-induced anxiety correlates with increased voluntary ethanol drinking. Human MRS studies report reduced cortical GABA levels in young adult binge drinkers. Heavy drinking, defined as exceeding recommended weekly limits (e.g., more than 15 standard drinks per week for men, 8 for women, leading to 0.1–0.2 g/dL blood alcohol concentration), leads to neuronal atrophy and reduced white matter integrity, associated with increased risks for dependence, anxiety, depression, cognitive deficits, impaired drinking control, and other health issues.

Behavioral changes observed in AUD are primarily attributed to plastic alterations of GABAA receptors following chronic ethanol exposure, including significantly reduced postsynaptic α1 subunits and increased α4-containing GABAA receptors. The subunit composition of GABAA receptors influences their physiological properties and pharmacological profiles. Studies using genetically engineered mice demonstrate that the α1 subunit mediates sedation, anti-convulsant activity, and anterograde amnesia, while the α4 subunit is involved in mood and anxiety changes. These GABAA receptor subunit composition changes represent a mechanism underlying behavioral shifts after chronic ethanol exposure, which increases the risk of developing dependence. Heavy drinking, often triggered by chronic stress and associated anxiety, is an additional risk factor for alcohol dependence in both animal models and humans. Conversely, reducing or stopping alcohol consumption can exacerbate stress or anxiety due to an overall imbalance in brain homeostasis.

Chronic alcohol consumption escalates the risk for reward-associated habitual alcohol use, pronounced craving, and an inability to cease alcohol seeking. This is strongly linked to the development of dependence, a severe form of AUD characterized by tolerance and continued consumption to avert withdrawal symptoms. Alcohol dependence is a serious condition requiring comprehensive treatment for its physical, emotional, and behavioral components. Postmortem studies reveal a loss of GABAergic markers in the brains of adults with alcohol dependence, particularly in men. Transcranial magnetic stimulation (TMS) studies suggest chronic alcohol dependence impacts GABAA and GABAB receptor function, with findings varying across studies. While some studies report no effects on short-interval cortical inhibition or TMS-evoked N45 potential, which index GABAA receptor function, others demonstrate a general decrease in GABA levels, including in youth with alcohol dependence. Given the dynamic nature of alcohol's effects on GABA, levels depend on factors such as recent detoxification or prolonged abstinence, and individual traits like age. One report indicated decreased long-interval cortical inhibition, thought to index GABAB function, in alcohol-dependent patients. Numerous preclinical studies confirm that chronic ethanol consumption alters GABAA receptor plasticity, leading to ethanol dependence. Other preclinical research establishes that general GABAA receptor expression and function change in cases of alcohol dependence, both synaptically and extrasynaptically, in brain regions crucial for dependence and symptom emergence (e.g., cortex, hippocampus, central amygdala). This translates to a general loss of phasic and tonic GABAergic inhibition, tolerance to ethanol, and cross-tolerance to benzodiazepines and other sedative-hypnotics acting on GABA receptors. Such alterations in overall GABAergic functioning lead to a significant excitation/inhibition imbalance across multiple brain regions, resulting in decreased inhibitory control over neurotransmitter firing activity. This contributes to various behavioral changes, including cognitive deficits, seeking behavior, and mood changes. Chronic alcohol consumption in heavy drinking, dependence, and associated GABAA plasticity changes also lead to alterations in dopamine release within reward neurocircuitry. During acute alcohol withdrawal, changes include upregulation of α4-containing GABAA receptors and downregulation of α1- and α3-containing GABAA receptors. GABAA receptor downregulation may contribute to anxiety and seizures during withdrawal. During withdrawal, rats exhibit a significant decrease in dopamine and serotonin levels in the reward neurocircuitry, commonly associated with dysphoria, depression, and anxiety disorders. These psychological changes may also contribute to ethanol-seeking behavior, highlighting the complex changes induced by chronic alcohol consumption.

5. Existing Interventions

Current therapeutic interventions for AUD and alcohol withdrawal aim to leverage the various CNS systems affected by alcohol to mitigate associated harms. These interventions exhibit diverse efficacy levels, side effects, and contraindications. Several clinical trials have demonstrated the efficacy of approved pharmacotherapies for AUD or withdrawal, and some are used off-label.

Non-GABAergic pharmacological interventions include Disulfiram, an FDA-approved drug since 1951, which inhibits acetaldehyde dehydrogenase, leading to unpleasant side effects upon alcohol consumption and thereby deterring drinking. However, Disulfiram carries risks such as hepatotoxicity and death, requiring cautious use. Naltrexone (Revia®), a competitive μ opioid receptor antagonist, is widely used, reducing craving by diminishing alcohol's rewarding and euphoric effects. It is generally well tolerated with minor side effects. Acamprosate, an FDA-approved drug in Europe and North America, is used for alcohol craving and relapse prevention. While its exact mechanism is unclear, it is thought to reduce glutamate during alcohol withdrawal through NMDA receptor modulation and indirectly potentiate GABAA receptors, generally with good tolerability. Nalmefene, another antagonist of μ and δ opioid receptors and partial agonist at the κ receptor, is approved for AUD in Australia and Europe. It reduces dopamine release in the NAc, decreasing alcohol dependence and consumption by lessening rewarding and craving effects. Nalmefene can aid in controlling alcohol intake, showing improved results with psychosocial support, and typically has mild, transient side effects.

GABAergic pharmacological interventions include Baclofen, approved in France for alcohol withdrawal treatment. Despite trials supporting its efficacy in reducing relapse risk and increasing abstinence days, its overall efficacy remains controversial, with some reviews finding insufficient evidence. Baclofen acts as a GABAB receptor agonist, decreasing dopamine release in the mesolimbic system, which reduces craving and withdrawal symptoms. However, it has multiple side effects that limit its use. Gabapentin, a GABA analog used as an anti-epileptic, has shown dose-dependent efficacy in clinical trials for reducing craving, anxiety, and facilitating abstinence. Concerns exist regarding its sedating properties and extra-medical use, and it can cause respiratory depression, increasing opioid-related deaths when combined with opioids. Despite being a GABA analog, its mechanism of action is unclear, primarily targeting the α2δ-subunit of voltage-gated calcium channels and increasing brain GABA concentrations. Topiramate, though not yet FDA-approved for AUD, has demonstrated reductions in craving, relapse risk, and increased abstinence in clinical trials. It is an approved anti-convulsant for epilepsy, believed to act through GABAA receptor modulation. It also binds to the AMPA receptor to decrease glutamate release and reduces dopamine release in the NAc. Side effects include paresthesia, taste disturbance, anorexia, and cognitive impacts such as mental and physical slowing and concentration difficulties. Benzodiazepines (BZ) are allosteric modulators of the GABAA receptor, enhancing GABA activity. They are recommended for managing acute alcohol withdrawal but not for AUD treatment due to their potential for sedation, ataxia, anterograde amnesia, and abuse. Alcohol delays BZ metabolism, prolonging their bioavailability, causing psychomotor impairment, and increasing overdose risk. BZ also modulate ethanol's reinforcing and/or aversive properties, and co-consumption with ethanol amplifies alcohol's effects.

Psychotherapeutic interventions offer alternative approaches. Cognitive Behavioral Therapy (CBT) is a form of psychotherapy that challenges automatic thoughts, cognitive distortions, existing beliefs, and problematic behaviors. It is one of the most studied and evidence-supported treatments for SUD. Adults with problematic drinking receiving CBT show decreased alcohol consumption, with newer variants like virtual reality-assisted CBT demonstrating greater success than traditional methods. Motivational Enhancement Therapy (MET) is a psychosocial treatment applying motivational psychology principles, often forming the basis for brief interventions for risky alcohol use. MET focuses on identifying reasons for changing alcohol consumption, with outcomes varying based on commitment and readiness for change.

However, existing therapeutic options often have limitations. Some drugs, repurposed from other indications, directly or indirectly affect the GABAergic system (e.g., Gabapentin, Topiramate, Baclofen). The GABAergic system is a crucial player in AUD pathophysiology and alcohol withdrawal, making it a desirable target for drug development. The intricate relationship between central pathways in ethanol consumption and the instrumental role of the GABAergic system in modulating most effects, directly or indirectly, highlights its importance. However, AUD is diverse in its manifestations (e.g., volume consumed, acute vs. chronic), and ethanol's impact on the GABAergic system may vary accordingly. This suggests that different interventions targeting distinct aspects of the GABAergic system may be necessary for optimal outcomes in treating AUD or alcohol withdrawal.

6. GABAergic Interventions in Preclinical Models and Their Impact on Alcohol-Related Symptoms: Reconciling Risk and Benefits

Given ethanol's facilitation of GABA activity and its extensive effects on GABAergic receptor expression and function, predicting the impact of a GABAergic drug on individuals with AUD can be challenging. Benzodiazepines (BZs), which bind at the interface of α1-2-3-5 and γ subunits of GABAA receptors, enhance phasic GABAergic inhibition across brain regions and induce internalization of synaptic GABAA receptors. While BZs promote mechanisms contributing to some ethanol-induced deficits in GABAergic inhibition, they offer beneficial effects in acute withdrawal by acting as a substitute for ethanol, helping individuals re-establish a new excitation/inhibition balance without alcohol.

In recent years, BZ-derivatives that preferentially target selected α-subunits have been developed and tested in preclinical models for their effects on ethanol self-administration and craving. Studies on ethanol discrimination showed that activation of α2/α3-GABAA receptors by PAMs (HZ-166, XHe-II-053, YT-III-31, or YT-III-271) augmented the reinforcing effects of ethanol, increasing self-administration in rhesus monkeys. These findings align with clinical evidence linking GABRA2 and GABRA3 gene expression to an increased risk for alcoholism. Similarly, potentiation of the α5-GABAA receptor by QH-ii-066 administration enhanced alcohol's reinforcing effects in non-human primates, whereas an inverse agonist (Xli-093) inhibited these effects. Consistent with this, intra-hippocampal infusions of an α5-GABAA receptor inverse agonist (RY023) dose-dependently reduced ethanol-maintained responses, suggesting a significant role for α5-GABAA receptors in the hippocampus in regulating ethanol-seeking behaviors. This is further supported by studies using the partial α5-GABAA receptor inverse agonist Ro 15–4,513, the selective α5-GABAA inverse agonist (α5IA-II), and α5-GABAA receptor knockout mice models, all showing reduced ethanol preference. However, these studies primarily evaluated positive modulation of αx-GABAA receptors in the context of alcohol consumption or discrimination, when the system is already sensitized to further GABAergic activity. It remains unclear how such modulation would function during withdrawal, when the system is deficient in GABAergic regulation and experiencing craving behaviors. Given the anti-craving effect of BZ, α2-, α3-, or α5-PAMs could potentially contribute to BZ's anti-craving effects in a withdrawal state, potentially offering benefits without the typical side effects of benzodiazepines. While BZ and their derivatives bind at the α1-2-3-5 and γ subunits, neurosteroids bind between the α and β subunits of GABAA receptors, with their binding significantly facilitated by the presence of the δ subunit. Neurosteroids are potent neuromodulators synthesized from cholesterol in glial and neuronal cells of both the central and peripheral nervous systems. They act at extrasynaptic receptors, facilitating tonic inhibition. Acute alcohol intake increases cerebral allopregnanolone levels, which are reduced during chronic alcohol consumption and withdrawal. Stimulation of neurosteroidogenesis by metyrapone has been shown to reduce cocaine intake in rats, suggesting a potential similar effect for alcohol. Recent studies indicate that allopregnanolone possesses antidepressant properties for women with postpartum depression, a disorder associated with reduced GABAergic function. Therefore, given their action on the GABAergic system and their involvement in arousal, cognition, emotion, and motivation, neurosteroids may hold therapeutic potential in treating AUD, with current investigations exploring these effects.

The involvement of GABAB receptors in AUD development is still being clarified. However, studies in clinical populations (using Baclofen) and animal models show that GABAB receptor modulation benefits AUD management. For example, rats receiving baclofen exhibited reduced hyper-locomotion caused by acute alcohol administration and diminished anxiety-like behavior and tremors following chronic alcohol withdrawal. Various GABAB PAMs, such as CGP7930, GS39783, BHF177, Rac-BHFF, ADX71441, CMPPE, COR659, and ORM-27669, have been studied in rodent models and found to be beneficial in AUD.

7. Novel Therapeutic Agents Targeting the GABAergic System in Clinical Trials

With the increased characterization of alcohol's impact on the GABAergic system and the growing understanding of the link between GABAergic functions, receptor subtypes, and symptom relief in AUD, more clinical trials are being initiated to investigate how GABAergic modulation can contribute to improved AUD and alcohol withdrawal treatment.

Interventions targeting GABAA receptors are being investigated in multiple clinical trials. For example, Diazepam (DZ) is already the standard of care for reducing withdrawal symptoms. Midazolam, another benzodiazepine, and propofol, a GABAA receptor agonist, were previously studied for their potential effects on stress response and immune functions in mechanically ventilated AUD patients but were withdrawn from Phase 4 studies due to logistical reasons. Brexanolone, a GABAA-targeting neurosteroid already approved for treating postpartum depression, is preparing for a Phase 1 study to assess its safety before evaluating efficacy in participants with AUD and PTSD. Baclofen, a GABAB agonist, is currently in Phase 4 to assess its efficacy in managing acute alcohol withdrawal. Although approved in France for reducing craving and withdrawal syndrome, some literature suggests its efficacy for this indication is limited. ASP8062, a GABAB-PAM, is undergoing a Phase 2 study to investigate the efficacy of two weeks of treatment in participants with moderate AUD for reducing alcohol cravings. Preclinical studies in rats showed promising effects in reducing alcohol self-administration without the side effects observed with baclofen, and human Phase 1 studies confirmed ASP8062's safety. The antiepileptic valproate also indirectly affects the GABAergic system by blocking GABA metabolism and reuptake, thereby increasing brain GABA levels. Clinical trials are ongoing to determine valproate's efficacy in reducing ethanol withdrawal compared to benzodiazepines, such as lorazepam. Lorazepam was also used in an open-label clinical trial completed in 2013 to assess the efficacy of its combination with disulfiram, which reported a significant reduction in anxiety, depression, and craving 24 weeks post-intervention.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neurostimulation modality delivering focused magnetic field pulses to the cortex, modulating cortical activity. Treatment sessions, typically delivered daily over several weeks, induce long-term neuroplastic changes in cortical excitability, including modulation of neurocircuits implicated in alcohol use disorder, making it a potential treatment under investigation. Enduring changes in cortical activity (inhibition and excitation) resulting from rTMS have implications for sustained changes in GABA activity. Over a decade ago, the first published clinical trial demonstrated rTMS's efficacy in reducing cravings in adults with AUD compared to a sham-control condition. Since then, most trials have applied rTMS over the left or right dorsolateral prefrontal cortex, with a recent meta-analysis indicating a signal for reduced alcohol craving with rTMS treatment, potentially driven by its impact on GABAergic signaling. However, most randomized controlled trials (RCTs) have been small, single-center studies, and given the substantial heterogeneity in parameters used, the optimal protocol remains undetermined. Additionally, there is growing interest in deep rTMS™ using H Coils, which can induce a broader electrical field within the cortex. For instance, a recent RCT using rTMS with an H7 Coil stimulating the bilateral medial prefrontal cortex and anterior cingulate cortex showed positive results in reducing craving and alcohol consumption in treatment-seeking AUD patients. Another trial using a coil that stimulates the bilateral lateral prefrontal cortex and insula demonstrated efficacy for nicotine dependence in a large, definitive, multi-site RCT, leading to FDA clearance for this indication, marking the first FDA-cleared indication for any substance use disorder. Collectively, further exploration of rTMS's therapeutic potential for AUD is warranted. Given the well-described link between GABA dysfunction in AUD and rTMS effects on the GABAergic system, it will be important to investigate whether biomarkers of GABAergic functions can serve as mediators or moderators of rTMS efficacy.

8. Conclusion

Alcohol use-related disorders are significant risk factors for other diseases associated with high mortality. Although the precise mechanisms are still being elucidated, the GABAergic system appears to play a critical role in AUD development. Currently, GABAergic drugs are utilized as second or third-line treatments for AUD and for mitigating alcohol withdrawal symptoms. Studies indicate that pharmacological modulation of GABA receptors holds promise as a therapeutic option for achieving long-term abstinence by reducing daily alcohol intake and alleviating withdrawal effects. However, extensive research is still needed to fully uncover the pharmacological potential of the GABAergic system in managing alcohol use-related disorders.

GABAergic Signaling in Alcohol Use Disorder and Withdrawal

Alcoholic beverages have been consumed for recreation globally for a long time. Current estimates indicate that a significant portion of the global adult population experiences alcohol use disorders (AUD). Ethanol, the main active component in alcohol, produces effects like anxiety reduction and disinhibition, which are often sought after in social settings or by individuals with AUD. However, alcohol consumption is also linked to approximately 230 diseases, including various cancers, heart diseases, mental disorders, and injuries. Abstaining from alcohol offers health benefits, while increased consumption raises risks for certain cancers, heart disease, and stroke. Chronic high-dose ethanol use is also associated with low mood, thinking problems, and a higher chance of developing AUD.

Two major systems define AUD: the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which describes AUD by behavioral and physical symptoms like withdrawal, tolerance, and craving; and the International Classification of Diseases 11th Revision (ICD-11), which categorizes it into harmful use and dependence. AUD symptoms involve poor drinking control, impulsivity, reduced response to natural rewards, and continuing use despite negative outcomes. Due to the brain's reliance on alcohol in AUD, stopping drinking often leads to withdrawal symptoms, which can range from mild issues like insomnia and anxiety to severe effects like delirium and seizures, often due to brain hyperexcitability. Ethanol and its breakdown products affect multiple brain pathways, particularly those involving gamma-aminobutyric acid (GABA), making this system a key focus for treatment.

How Ethanol Affects the Brain's Neurotransmitters

Ethanol produces various behavioral and physiological effects by binding to and influencing many proteins, receptors, and signaling pathways throughout the brain. Its primary targets, responsible for effects like reduced inhibition and anxiety relief, are GABAA receptors. Beyond directly affecting GABAA receptors, ethanol also modulates ionotropic glutamaterergic receptors and can indirectly influence other brain chemicals like dopamine, serotonin, and opioids, especially in reward-related brain regions. With chronic alcohol consumption, the brain adapts to maintain balance, leading to a new state where ethanol becomes crucial for neuronal function. This adaptation results in increased tolerance to alcohol and often lower levels of GABA in the brain.

The main impact of ethanol is thought to be on the glutamatergic (excitatory) and GABAergic (inhibitory) signaling pathways, causing an overall imbalance in neuronal activity. This imbalance is believed to contribute to "blackouts" after heavy drinking and can lead to over-excitation and reduced brain plasticity. GABA, the brain's main inhibitory neurotransmitter, functions by binding to two types of receptors: GABAA and GABAB. GABAA receptors facilitate fast inhibition and are the primary site where ethanol acts as a positive modulator, explaining its sedative effects. GABAB receptors mediate slower inhibition and are also affected by alcohol, though the exact mechanism is less understood. Ethanol's metabolites, such as acetaldehyde and salsolinol, also contribute to its effects by influencing dopamine and opioid systems, but their specific actions on the GABAergic system require further investigation.

Alcohol Use Patterns and the GABAergic System

Different patterns of alcohol consumption, from occasional use to severe dependence, all influence the brain's GABAergic system. Even low-risk or moderate alcohol intake can enhance the action of GABA at GABAA receptors, leading to feelings of relaxation and affecting receptor expression in the brain. As consumption increases, for example in medium-risk drinking, ethanol further potentiates GABAA receptors, decreasing excitatory signals and causing mild sedation, memory changes, and mood shifts. At-risk drinking activates the brain's reward pathways more strongly, fostering the development of alcohol's addictive properties.

Binge drinking, consuming large amounts of alcohol quickly, leads to thinking difficulties and reduced control over drinking. Studies show that binge drinking can decrease GABA levels in the brain and alter the composition of GABAA receptors. Heavy drinking, defined by consistently high weekly intake, causes brain changes like reduced neuronal tissue and impacts white matter, increasing the risk for dependence, anxiety, depression, and cognitive problems. The changes in GABAA receptor subunit composition are thought to contribute to these behavioral changes. Chronic daily alcohol use often leads to dependence, a severe form of AUD where tolerance develops, and individuals drink to avoid withdrawal symptoms. Studies indicate a loss of GABAergic markers in the brains of those with alcohol dependence and alterations in GABAA and GABAB receptor function. This results in a general decrease in GABAergic inhibition, contributing to tolerance, cross-tolerance to other sedatives, and an imbalance in brain activity that leads to various behavioral changes, including cognitive deficits and mood shifts. During withdrawal, changes in GABAA receptors, along with reduced dopamine and serotonin levels, contribute to feelings of low mood and increased cravings.

Current and Future Treatments for Alcohol Use Disorder

Existing treatments for AUD and alcohol withdrawal aim to address the various brain systems affected by alcohol. Non-GABAergic medications include disulfiram, which causes unpleasant reactions if alcohol is consumed; naltrexone and nalmefene, which reduce cravings by blocking opioid receptors; and acamprosate, which decreases glutamate activity during withdrawal. GABAergic medications include baclofen, a GABAB agonist approved in some regions for withdrawal management, though its overall efficacy is debated. Gabapentin, a GABA analog, can reduce craving and anxiety, but its exact mechanism is not fully understood. Topiramate, an anti-convulsant, reduces craving and relapse by modulating GABAA receptors and decreasing glutamate. Benzodiazepines (BZ) are commonly used for acute alcohol withdrawal due to their ability to enhance GABAA receptor activity, but they carry risks of sedation, amnesia, and abuse potential.

Psychotherapeutic interventions such as Cognitive Behavioral Therapy (CBT) and Motivational Enhancement Therapy (MET) are effective behavioral treatments that help individuals challenge problematic thoughts and behaviors related to alcohol use. Research is also exploring new GABAergic interventions. Preclinical studies are investigating specific GABAA receptor subunits and GABAB receptor modulators for their potential to reduce alcohol intake and craving without the side effects of current drugs. Neurosteroids, such as brexanolone, which act on GABAA receptors, are also being studied for AUD. In clinical trials, brexanolone is being investigated for AUD and PTSD, and ASP8062, a GABAB modulator, is in Phase 2 for reducing alcohol cravings. Valproate, an anti-epileptic drug that increases brain GABA levels, is also being studied for alcohol withdrawal. Beyond medication, non-pharmacological approaches like repetitive transcranial magnetic stimulation (rTMS), which uses magnetic pulses to modulate brain activity, are being explored for their potential to reduce alcohol craving, possibly by affecting GABAergic signaling.

Conclusion

Alcohol use disorders pose significant risks to health and are linked to other serious diseases. While the exact mechanisms are complex, the GABAergic system plays a crucial role in the development and symptoms of AUD. Current GABAergic drugs are used in AUD treatment and for managing alcohol withdrawal. Ongoing research suggests that directly influencing GABA receptors could be a promising way to help individuals achieve long-term abstinence by reducing daily alcohol intake and easing withdrawal effects. Extensive research continues to explore the full therapeutic potential of the GABAergic system in managing alcohol-related disorders.

The Brain's GABA System in Alcohol Use Disorder and Recovery

Introduction to Alcohol Use Disorders and GABAergic Signaling

Alcoholic beverages have been consumed for recreation around the world for many centuries. Recent global estimates suggest that a notable portion of the adult population lives with alcohol use disorders (AUD). Ethanol, the main active part of alcohol, is a widely used drug that can reduce anxiety and lower inhibitions. However, alcohol consumption is also linked to about 230 diseases and disorders, including cancer, heart disease, mental health issues, and injuries. Studies indicate that even low amounts of alcohol may not offer protective health benefits, and stopping alcohol use can lead to improved health, such as better sleep. Increased alcohol consumption raises the risk of certain cancers, heart disease, and stroke. Chronic, heavy drinking is also connected to feelings of unhappiness, thinking problems, and a higher chance of developing AUD.

Two main systems define AUD: the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) describes it as a group of behavioral and physical symptoms like withdrawal, tolerance, and craving. The International Classification of Diseases (ICD-11) splits AUD into harmful alcohol use and alcohol dependence, which involves a strong drive to use alcohol, difficulty controlling use, prioritizing alcohol over other activities, and continuing to use it despite harm. Globally, millions of adults, particularly men, are affected by AUD.

AUD can involve the brain developing tolerance and a need for alcohol, leading to compulsive seeking and withdrawal symptoms when consumption stops. Symptoms can include poor control over drinking, impulsivity, reduced response to natural rewards, learning harmful patterns, negative emotional states during withdrawal, poor decision-making, and automatic responses. Because the brain of someone with AUD relies on alcohol for normal function, stopping can cause withdrawal. Sudden cessation can lead to severe symptoms like delirium, seizures, and cognitive problems. The severity of withdrawal symptoms varies based on how much and how long alcohol was consumed, and individual differences. These symptoms often relate to overexcitement in the brain, such as insomnia, anxiety, and even seizures, likely due to changes in the brain's inhibitory system.

Ethanol easily enters all parts of the body, including the brain. It is processed mainly in the liver but also in the brain, producing substances like acetaldehyde and acetate. Once in the brain, ethanol and its byproducts disrupt processes, leading to changes in various brain chemicals, including dopamine, GABA, and glutamate. Since alcohol affects many brain pathways, different treatments have been developed, but there is still a need to better understand AUD and create more effective strategies. While alcohol impacts many pathways, one of the main ones it changes is the inhibitory pathway, which uses a chemical called gamma-aminobutyric acid (GABA).

This document will review how ethanol affects brain functions related to GABA, discuss current treatments and their limitations, and summarize what is known about GABA's role in AUD symptoms and potential future treatments that target the GABA system.

How Alcohol Affects the Brain

Ethanol causes many behavioral and physical effects, though its exact mechanisms are not fully understood. Like most addictive substances, ethanol interacts with multiple proteins, receptors, and signaling pathways throughout the brain. The primary targets for alcohol's effects, such as reduced inhibition, increased activity, and lower anxiety, are GABAA receptors. Besides changing GABAA receptor activity, ethanol can directly bind to and affect other proteins, including glutamate (NMDA) receptors. It can also indirectly change the activity of other brain chemicals like dopamine, serotonin, and opioids, especially in brain areas involved in the reward system.

As a result, long-term heavy alcohol use creates a chemical imbalance in the brain, forcing it to adapt to maintain normal function. When the brain adjusts to too much ethanol, it forms a new balance where alcohol becomes essential for nerve activity. In individuals with AUD, this leads to increased tolerance to alcohol's effects, potentially causing them to drink near toxic levels to feel relaxation or reduced anxiety. Consistent with this, brain imaging studies often show lower GABA levels in the brain's outer layer in people with AUD, especially during withdrawal. Therefore, ethanol's main impact is thought to be on pathways using glutamate and GABA, leading to either increased or decreased activity depending on whether alcohol use is acute, chronic, or during withdrawal. This can then trigger a chain of events affecting the release of dopamine, serotonin, and natural opioids.

Studies have shown that ethanol binds to and reduces the function of glutamate receptors, while it binds to and helps the function of GABAA and GABAB receptors. This combination causes an overall imbalance in nerve activity, which is believed to cause "blackouts" after heavy drinking and contribute to nerve damage and reduced brain flexibility. Brain stimulation studies in humans have confirmed that alcohol increases GABA-related inhibition and decreases glutamate-related excitement in the brain. Interestingly, the effects of alcohol's breakdown products on glutamate and GABA targets seem to differ, which might explain the changing effects seen during drinking. Studies in animals have also confirmed alcohol's significant impact on GABAA receptor signaling in a brain region called the amygdala, which plays a critical role in how alcohol cravings are maintained. Animal studies have also confirmed alcohol's effects on behaviors like compulsive actions, anxiety, and thinking problems, as well as on brain chemicals like GABA, glutamate, and dopamine, offering insights for treatments.

Alcohol intake in animals has also been shown to bind to a type of acetylcholine receptor and increase acetylcholine levels in a brain area involved in reward, which helps explain why alcohol consumption can be reinforcing. Effects on other brain regions are thought to contribute to negative effects. Alcohol's binding to these receptors may also interfere with nicotine's effects, which could explain why alcohol and tobacco are often used together.

As an indirect effect of alcohol use, ethanol causes an increase in dopamine release, a brain chemical linked to reward and motivation. Studies in animals have shown that dopamine is released in brain areas involved in reward, which can be further increased by using nicotine. The activation of brain GABA signals, especially through GABAB receptors, is also connected to dopamine activity during rewarding processes, all contributing to alcohol's addictive properties.

Acute alcohol use also increases serotonin release, which adds to alcohol's rewarding effects. Studies have shown that acute ethanol increases the firing rate of certain serotonin receptors, and longer-term use can affect the function of other types of serotonin receptors.

Consuming alcohol has also been shown to increase levels of natural opioids in the body, which then drop sharply during withdrawal, leading to cravings and an increased risk of seeking opioids. Alcohol's effect on GABAA receptors in brain regions linked to reward helps release these natural opioids, contributing to the feeling of euphoria from alcohol. Opioid-targeting treatments can reduce these effects of alcohol, further supporting alcohol's impact on the opioid system.

The breakdown products of ethanol—acetaldehyde, salsolinol, and acetate—also seem to play a role in alcohol's effects, though their contributions are less understood. Acetaldehyde in the brain causes a feeling of euphoria at low doses and is important for alcohol's reinforcing properties, helping to cause addiction. It has been shown to increase GABA uptake and stimulate dopamine neurons and opioid receptors. Salsolinol may also produce some of alcohol's effects by activating opioid receptors on GABA neurons, but its actions are complex; it appears to reduce GABA activity while ethanol increases it, suggesting opposite effects on GABA receptors and, consequently, on dopamine release. The direct role of acetate on GABA regulation has not been fully reported, but it is known to increase blood flow in the brain and enhance nerve excitement, while ethanol boosts GABA-mediated inhibition. More research is needed to confirm the effects of alcohol's breakdown products on the GABA system.

The Role of GABA in Alcohol Use Disorders

GABA is the main chemical that slows down brain activity. It works by binding to two types of receptors: GABAA and GABAB. GABAA receptors are channels that let chloride ions into cells, causing a quick slowing effect. GABAB receptors are different types of receptors that cause a slower inhibitory effect. Both GABAA and GABAB receptors have been extensively studied for their potential in drug treatments and their connection to AUD.

GABAA receptors are made up of five parts from various subunits and are found throughout the brain, including areas involved in alcohol use like the prefrontal cortex and amygdala. Ethanol acts as a positive modulator of GABAA receptors, meaning it enhances their activity by binding to several of their parts, especially the alpha subunits. This explains its sedative and brain-modulating effects. Other positive modulators include common anxiety medications that cause sedation, anxiety reduction, muscle relaxation, and seizure prevention.

GABAB receptors are the only other main type of receptor for GABA and are found in many parts of the brain and body. For GABAB receptors to work, two main parts must connect to form an active unit. Medications that affect GABAB receptors can help prevent seizures and reduce pain. They are also known to decrease cravings and withdrawal symptoms in individuals who are dependent on alcohol.

Alcohol Use Patterns and Their Impact on the GABAergic System

The DSM-5 classifies substance-related disorders by severity based on symptoms, ranging from mild to severe. This discussion will use common categories of alcohol use to better explain how AUD affects the body and the GABA system. AUD includes various disorders with different drinking patterns that impact the brain and its GABA system. Even minimal alcohol use, not meeting AUD criteria, affects the GABA system. For example, a small amount of alcohol in the brain can affect GABAA receptors, causing a chain of changes that might lead to behavioral shifts. When drinking becomes chronic or involves heavy binge episodes, alcohol's impact on the brain becomes much more significant, activating or inhibiting other biological pathways.

For men, consuming less than two drinks per day, and for women, less than one drink per day, is generally considered safe or moderate use, with a low risk of developing AUD. Even at this low level, alcohol can enhance GABA's action at GABAA receptors, leading to feelings of relaxation. In animal studies, small amounts of alcohol can rapidly reduce the number of certain GABAA receptors in the brain. Other GABAA receptors may decrease hours after consumption, then increase after a few days, showing that even acute alcohol use has broad and lasting effects that are reversible, but the time for recovery depends on the amount consumed.

During medium-risk drinking, where alcohol is consumed in a short period but not to the point of binge drinking (e.g., not more than five drinks in two hours for men, or four for women), alcohol levels can cause slight sedation, a feeling of relief, minor memory and attention problems, and potential mood changes. Animal studies show that this level of alcohol increases the firing rate of GABA neurons in a brain area critical for motivation, reward, and addiction. This impact on the brain's reward system, possibly driven by changes in GABA activity, contributes to increased alcohol intake. Interestingly, animal studies also suggest that reducing the activity of certain GABAA receptors in the brain can reduce alcohol consumption, confirming the important role of GABA activity in increasing alcohol intake and seeking behaviors.

Drinking alcohol beyond the recommended safe and moderate levels is considered at-risk. In this scenario, ethanol activates GABAA receptors in various brain regions, leading to an overall imbalance where inhibition is increased. At a certain point, the brain's reward pathways become directly and indirectly activated, releasing dopamine, which helps develop alcohol's addictive properties.

AUD is diagnosed when drinking patterns exceed established standards, either in volume or frequency. A common tool to identify AUD is the Alcohol Use Disorder Identification Tool (AUDIT). While the classification of AUD has evolved, most professionals often categorize it into binge drinking and heavy drinking.

Binge drinking involves consuming large amounts of alcohol quickly (e.g., five or more drinks in less than two hours for men, or four or more for women). This can lead to thinking problems, reduced self-control, and a decreased ability to voluntarily limit alcohol intake, increasing the likelihood of more frequent AUD in the future. Risk factors include age, being male, starting alcohol consumption at a young age, mental health status, and genetics. Animal studies show that binge drinking in young animals can cause anxiety-like behavior and lead to alcohol dependence in adulthood. Stress and anxiety during withdrawal are linked to increased alcohol drinking in animals. Human brain imaging studies have shown that GABA levels in the brain's outer layer are lower in young adults who binge drink. Other studies show that increasing GABA inhibition can help reduce binge drinking, confirming GABA's crucial role in limiting alcohol intake.

Heavy drinking is defined as drinking more than recommended during a week (e.g., more than 15 standard drinks weekly for men, or more than 8 for women). Heavy drinking leads to nerve damage and reduced integrity of brain white matter, which is associated with increased risk for dependence, anxiety, depression, cognitive problems, altered control over drinking habits, and other health risks. Studies show that these behavioral changes are mainly due to the changes in GABAA receptors after long-term alcohol exposure, including a significant reduction in certain GABAA receptors and an increase in others. These changes in GABAA receptor composition determine their properties and contribute to the behavioral shifts after chronic alcohol exposure, leading to further risks of developing dependence. Heavy drinking, especially when triggered by chronic stress and anxiety, is an additional risk factor for alcohol dependence in both animals and humans. Conversely, stopping or reducing alcohol consumption can worsen stress or anxiety due to an overall imbalance in brain function.

Chronic or daily alcohol use significantly increases the risk for habitual alcohol abuse linked to rewards, strong cravings, and an inability to stop seeking alcohol. This is often strongly connected to developing dependence, a severe form of AUD where a person becomes tolerant to alcohol's effects and continues drinking to avoid withdrawal symptoms. Alcohol dependence is a serious condition requiring comprehensive treatment for its physical, emotional, and behavioral aspects.

Studies of human brains after death have found a loss of GABA markers in adults with alcohol dependence, particularly in men. Brain stimulation studies have also shown that long-term alcohol dependence affects GABAA and GABAB receptor function, though results vary. Some studies found no effect on certain brain inhibition markers linked to GABAA function, while others reported a general decrease in GABA levels, especially in young people with alcohol dependence. Given alcohol's dynamic effects on GABA, GABA levels depend on factors like recent detoxification or longer abstinence, and age. One report on long-term brain inhibition, thought to be related to GABAB, showed decreases in alcohol-dependent patients.

Many animal studies have shown that chronic ethanol use changes how GABAA receptors adapt, leading to ethanol dependence. Other animal studies found that overall GABAA receptor function and expression change in cases of alcohol dependence, both at the connections between neurons and in other areas, in brain regions crucial for developing dependence and symptoms (like the cortex, hippocampus, and central amygdala). This results in a general loss of rapid and continuous GABA inhibition, tolerance to ethanol, and cross-tolerance to other sedatives that act on GABA receptors.

With such changes in overall GABA function, a significant imbalance between excitation and inhibition develops across multiple brain regions, causing a decrease in the brain's ability to control nerve firing. This leads to various behavioral changes, including thinking problems, seeking behavior, mood swings, and others. Chronic heavy alcohol use and the associated GABAA changes also lead to shifts in dopamine release in the brain's reward circuits. During acute alcohol withdrawal, changes occur, such as an increase in some GABAA receptors and a decrease in others. GABAA receptor reduction may contribute to anxiety and seizures during withdrawal. During withdrawal, animals show a significant drop in dopamine and serotonin levels in the reward circuits, commonly linked to unhappiness, depression, and anxiety disorders. These psychological changes can also contribute to alcohol-seeking behavior, showing the complex changes caused by chronic alcohol consumption.

Current Treatments for Alcohol Use Disorders

Existing treatments for AUD and alcohol withdrawal aim to influence the various brain systems that alcohol affects to reduce harm. These treatments have varying levels of effectiveness, different side effects, and reasons why they shouldn't be used. Several clinical trials have demonstrated the effectiveness of certain medications approved for treating AUD or withdrawal, and some are used for purposes not officially approved.

Medications Not Primarily Targeting GABA:

Disulfiram has been an approved medication for AUD for decades. It works by blocking an enzyme involved in alcohol breakdown, leading to higher levels of acetaldehyde in the blood. This causes unpleasant side effects if alcohol is consumed while taking the medication, discouraging further drinking. However, disulfiram can cause liver damage and, in rare cases, death, so it must be used carefully. Currently, one of the most widely used medications is naltrexone, which blocks certain opioid receptors. It reduces cravings by lessening the rewarding and euphoric effects of alcohol and is approved for AUD. It is generally well-tolerated with minor side effects.

Acamprosate is another approved medication for alcohol craving and relapse prevention. Although its exact mechanism is not fully known, it is believed to reduce glutamate during alcohol withdrawal and indirectly enhance GABAA receptors. Acamprosate is generally well-tolerated. Nalmefene also blocks opioid receptors and is approved for AUD in some countries. It reduces dopamine release in the brain's reward center, lessening alcohol dependence and consumption by decreasing the rewarding and craving effects of alcohol. It can help control alcohol intake and has shown better results when combined with psychological support. It has mild side effects that usually disappear over time.

Medications Targeting GABA:

Baclofen is approved in France for treating alcohol withdrawal. Despite studies supporting its effectiveness in reducing relapse and increasing abstinence, its overall efficacy remains debated, and some reviews consider the evidence insufficient. It acts on the GABAB receptor and reduces dopamine release in the brain's reward system, which lessens craving and withdrawal symptoms. However, baclofen has multiple side effects that limit its use.

Gabapentin is an older anti-epileptic drug. Clinical trials have shown it can reduce craving and anxiety and help achieve abstinence, with effects depending on the dose. However, concerns exist due to its sedating properties and reports of its misuse. It can also cause breathing problems alone and increases the risk of opioid-related deaths when combined with opioids. Despite being chemically similar to GABA, its exact mechanism is unclear and may not directly involve GABA. It seems to primarily target a specific calcium channel subunit and also increases GABA levels in the brain.

Topiramate is not yet approved for AUD, but clinical trials have shown it can reduce cravings and relapse risk and increase abstinence. It is approved as an anti-seizure medication and appears to work by modulating GABAA receptors. It also blocks a type of glutamate receptor to decrease glutamate release and reduces dopamine release. Side effects include tingling, altered taste, loss of appetite, and cognitive issues like slowed mental and physical activity and difficulty concentrating.

Benzodiazepines are medications that enhance the activity of GABAA receptors and are recommended for managing acute alcohol withdrawal, but not for long-term AUD treatment. They can cause sedation, problems with coordination, memory loss, and have a potential for abuse. Alcohol slows down the body's processing of benzodiazepines, prolonging their effects, causing coordination problems, and increasing the risk of overdose. Studies have also shown that benzodiazepines can modify some of alcohol's reinforcing or unpleasant effects, and combining them with alcohol can greatly amplify alcohol's effects.

Psychological Treatments:

In contrast to medications, Cognitive Behavioral Therapy (CBT) is a type of talk therapy that helps people challenge negative thoughts, distorted beliefs, and problematic behaviors. It is one of the most studied and supported treatments for substance use disorders. Adults with problematic drinking who received CBT showed reduced alcohol consumption, and newer versions of CBT, such as those using virtual reality, appear to be more successful than traditional methods.

Motivational Enhancement Therapy (MET) is another psychological treatment based on principles of motivation. MET often forms the basis of brief interventions for risky alcohol use and can be very short, involving only a few client-centered sessions. MET focuses on helping individuals identify reasons to change their alcohol consumption, but outcomes vary significantly depending on commitment and readiness to change.

Despite these options, existing treatments have limitations. Some drugs, originally used for other conditions, have direct or indirect effects on the GABA system. The GABA system is crucial in the development of AUD and alcohol withdrawal and is a promising target for new drug development. The previous sections showed how interconnected brain pathways are in alcohol use and how important the GABA system is in controlling most of alcohol's effects, directly or indirectly. However, AUD is diverse and can manifest in many ways (e.g., amount consumed, acute or chronic use). Therefore, alcohol's impact on the GABA system may vary with AUD manifestation, and different GABA-targeting treatments may be needed to achieve the best results in treating AUD or alcohol withdrawal. The following sections will discuss new GABA-focused treatments currently being researched.

New GABA-Targeted Treatments in Preclinical Studies

Since ethanol enhances GABA activity and greatly affects GABA receptor expression and function, predicting how a GABA-acting drug might impact individuals with AUD can be challenging. Benzodiazepines, which bind to specific parts of GABAA receptors, are known to boost GABA inhibition and can cause the receptors to be pulled into the cell. Thus, benzodiazepines promote some of the same brain changes that ethanol causes in GABA inhibition. However, benzodiazepines are beneficial for acute withdrawal symptoms because they can act as a substitute for alcohol, helping individuals in withdrawal regain a new balance in brain activity without alcohol.

In recent years, benzodiazepine-like drugs that act specifically on certain GABAA receptor subunits have been developed and tested in animal models for their effects on alcohol use and craving. Activation of certain GABAA receptors by specific drugs has been shown to increase alcohol's reinforcing effects in animals. These findings align with human studies suggesting that certain gene expressions related to these receptors are linked to an increased risk of developing alcoholism. Similarly, boosting another type of GABAA receptor also enhanced alcohol's reinforcing effects in animals, while blocking this receptor reduced them. Studies also showed that reducing the activity of these GABAA receptors in a brain region called the hippocampus lessened alcohol-seeking behaviors.

However, these studies mainly looked at the effects of boosting GABAA receptors in the context of alcohol consumption or alcohol preference when the brain system is already sensitized to more GABA activity. It remains unclear how such modulation would work during withdrawal when the GABA system is deficient, which causes cravings. Given that benzodiazepines can reduce craving, it is possible that these specific GABAA modulators could help with anti-craving effects during withdrawal without the side effects seen with traditional benzodiazepines.

While benzodiazepines and similar drugs bind and act at certain parts of GABAA receptors, neurosteroids bind at different parts. This binding is much easier when a specific subunit, the delta subunit, is present. Neurosteroids are powerful brain modulators made from cholesterol in brain cells. They act on receptors outside the main connections between neurons, creating a continuous calming effect. Acute alcohol intake increases brain levels of a neurosteroid called allopregnanolone, but its levels are reduced during chronic alcohol consumption and withdrawal. Increasing neurosteroid production has been shown to reduce cocaine intake in animals, suggesting a similar effect might occur with alcohol. Recent studies found that allopregnanolone has antidepressant properties for women with postpartum depression, a condition linked to reduced GABA function. Therefore, given their action on the GABA system and their involvement in arousal, thinking, emotion, and motivation, neurosteroids may offer a promising treatment for AUD, and these effects are currently being investigated.

The involvement of GABAB receptors in the development of AUD is still not fully understood. However, studies in both human patients and animals have shown that modulating GABAB receptors can be beneficial in managing AUD. For example, animals given baclofen showed reduced hyperactivity caused by acute alcohol and reduced anxiety and tremors after chronic alcohol withdrawal. Various GABAB-boosting drugs have been primarily studied in animal models and found to be beneficial in AUD.

New GABA-Targeted Treatments in Human Studies

With a better understanding of alcohol's impact on the GABA system and the link between GABA functions, receptor types, and symptom relief in AUD, more human clinical trials are being started to investigate how GABA modulation can lead to better treatment for AUDs and alcohol withdrawal. Treatments targeting GABAA receptors are being investigated in several clinical trials. For instance, a benzodiazepine called diazepam is already standard care for reducing withdrawal symptoms. Other benzodiazepines were studied for their potential effect on stress response and immune functions in hospitalized patients with AUD, but those studies were stopped for logistical reasons.

Brexanolone, a neurosteroid that targets GABAA, is preparing to recruit for an early-stage study to confirm its safety before testing its effectiveness in participants with AUD and PTSD. Brexanolone is already approved for treating postpartum depression.

Baclofen, a GABAB agonist, is currently in a late-stage study to assess its effectiveness in managing acute alcohol withdrawal. Although approved in France for reducing craving and withdrawal syndrome, some research suggests its effectiveness for this use is limited. Another drug, ASP8062, which boosts GABAB, is being studied in a mid-stage trial to see if two weeks of treatment can reduce alcohol cravings in people with moderate AUD. Early animal studies showed promising effects in reducing alcohol self-administration without the side effects seen with baclofen, and early human studies confirmed its safety.

The anti-epileptic drug valproate also indirectly affects the GABA system by blocking GABA breakdown and reuptake, which increases GABA levels in the brain. Clinical trials are underway to compare valproate's effectiveness in reducing ethanol withdrawal to that of benzodiazepines, specifically lorazepam. Lorazepam was also used in an earlier trial that combined it with disulfiram; reports showed a significant reduction in anxiety, depression, and craving observed several months after the intervention.

Non-Pharmacological Interventions – Repetitive Transcranial Magnetic Stimulation (rTMS):

Repetitive transcranial magnetic stimulation, or rTMS, is a non-invasive brain stimulation method that delivers focused magnetic pulses to the brain's outer layer to change its activity. Treatment sessions are usually given daily over several weeks, leading to long-term changes in brain excitability through brain plasticity. This includes changing the brain circuits involved in alcohol use disorder, and rTMS is being investigated as a potential treatment. Lasting changes in brain activity resulting from rTMS have implications for lasting changes in GABA activity. Over a decade ago, the first published clinical trial showed that rTMS could reduce cravings in adults with AUD compared to a placebo treatment. Since then, most trials have used rTMS over specific parts of the brain, with a recent analysis showing a signal for reduced alcohol craving with rTMS treatment, possibly due to its impact on GABA signaling. However, most of these studies have been small, single-center trials, and given the wide variety of settings used across studies, the best approach has not yet been determined.

Additionally, there is growing interest in using deep rTMS, which uses special coils to create a broader electrical field within the brain. For example, a recent study using deep rTMS stimulating certain brain areas showed positive results in reducing craving and alcohol consumption in patients seeking treatment for AUD. Another trial using a coil that stimulates different brain areas proved effective for nicotine dependence in a large, multi-center study, which led to its approval for that condition. This demonstrated the first approval for any substance use disorder. Together, these findings suggest that further exploration of rTMS for AUD is important. Given the clear link between GABA dysfunction in AUD and rTMS effects on the GABA system, it will be important to explore whether markers of GABA function can help explain or predict rTMS effectiveness.

Conclusion

Alcohol use-related disorders significantly increase the risk for other diseases that cause high mortality. Although the exact mechanisms are still being explored, the GABA system appears to be critically involved in the development of AUD. Currently, GABA-acting drugs are used as second or third-line treatments for AUD and to ease alcohol withdrawal. Studies indicate that using drugs to modify GABA receptors may be a promising treatment option for achieving long-term abstinence by reducing daily alcohol intake and withdrawal effects. However, extensive research is still needed in this area to fully uncover the treatment potential of the GABA system in managing alcohol use-related disorders.

GABA Signals in Alcohol Use Disorder and Withdrawal: How They Go Wrong and How They Can Help

Introduction

Today, about 5 out of every 100 adults around the world have problems with alcohol, known as alcohol use disorder (AUD). Drinking alcohol is also linked to about 230 different health problems, including heart disease, cancer, and mental health issues. While small amounts of alcohol might seem okay, newer studies show that even low amounts may not protect health and could still cause harm. Not drinking alcohol has many health benefits, like better sleep. Drinking a lot for a long time can lead to feeling down, trouble thinking clearly, and a higher chance of developing AUD.

AUD is when a person has trouble controlling their drinking. This includes having strong urges to drink, needing more alcohol to feel the same effects, and feeling sick when they stop drinking. It means a strong inner push to use alcohol, putting alcohol use before other things, and continuing to drink even when it causes harm. For example, in 2016, about 8.6 out of 100 adult men and 1.7 out of 100 adult women worldwide had AUD.

People with AUD often build up a tolerance to alcohol, meaning they need more of it. When they stop drinking, they can feel very sick. This sickness, called withdrawal, can range from not sleeping and feeling anxious to having seizures or seeing things that aren't there. The brain gets used to alcohol being around, and when it's gone, the brain becomes overactive.

Alcohol mixes easily with water, so it quickly gets into all parts of the body, including the brain. In the body, alcohol is broken down into other substances. Once in the brain, alcohol and what it breaks down into can change how the brain uses sugar and other important chemicals. One main chemical pathway that alcohol affects is the one that uses GABA. GABA helps calm the brain down.

Because alcohol affects many parts of the brain, different ways to treat AUD have been tried, but more help is still needed. This paper will explain how alcohol affects GABA in the brain, describe current treatments, and talk about new ideas for treatments that focus on the GABA system.

How Alcohol Affects the Brain

Alcohol causes many changes in the body and mind, but scientists are still learning exactly how. Alcohol acts on many different proteins, signals, and parts of the brain, including those that handle feelings, pain, and how cells talk to each other. The main way alcohol makes people feel less held back and less worried is by affecting GABA receptors in the brain. Alcohol can also directly change how other brain signals work.

Alcohol also indirectly changes other brain chemicals like dopamine, serotonin, and opioids, especially in parts of the brain linked to pleasure and reward. Because of this, drinking a lot of alcohol for a long time can cause a chemical problem in the brain. The brain then tries to fix this by getting used to the alcohol. When this happens, alcohol becomes a part of how the brain works. This leads people with AUD to need more alcohol to feel its effects, sometimes drinking dangerous amounts just to relax. Studies often show that people with AUD have lower levels of GABA in their brains, especially when they are going through withdrawal.

The main way alcohol works is by changing the signals of glutamate and GABA. Glutamate usually makes brain cells more active, and GABA calms them down. Alcohol increases GABA's calming effect and decreases glutamate's exciting effect. This can lead to memory blackouts after heavy drinking and damage to brain cells over time. Studies on people show that drinking alcohol increases GABA's calming effect and lowers glutamate's exciting effect. The substances that alcohol breaks down into can have different effects on these brain chemicals.

Animal studies have also shown that alcohol affects how GABA works in brain areas linked to alcohol seeking and withdrawal. Alcohol also changes other brain chemicals like acetylcholine, which is involved in reward, and can make people want to drink more, especially if they also use tobacco.

Alcohol also causes a rise in dopamine, a brain chemical linked to reward and motivation. This can make drinking feel good and increase the chances of addiction. The way alcohol affects GABA also plays a part in this dopamine release, adding to the addictive nature of alcohol. Drinking alcohol also increases serotonin and opioid levels, which contribute to the good feelings. But when someone stops drinking, these levels drop, leading to cravings. Medicines that block opioid effects can reduce these cravings, showing how much alcohol affects the opioid system.

The substances alcohol breaks down into in the brain can also affect how you feel. For example, acetaldehyde can cause good feelings at low levels and plays a big role in why alcohol is addictive. It can also affect dopamine and opioid signals. Another substance, salsolinol, might have opposite effects on GABA compared to alcohol, leading to different changes in dopamine. The third substance, acetate, seems to make brain cells more active and increase glutamate, which is the opposite of what alcohol does to GABA. More research is needed to fully understand how these substances affect the GABA system.

How GABA Works in Alcohol Use Disorder (AUD)

GABA is the main calming chemical in the brain. It works by attaching to two main types of receivers called GABAA and GABAB. GABAA receivers cause quick calming effects, while GABAB receivers cause slower calming effects. Both types of GABA receivers are found all over the brain, including areas involved in alcohol problems like the front part of the brain, a part called the thalamus, and the emotional part of the brain.

Alcohol works by helping GABAA receivers work better. It attaches to different parts of these receivers, which helps explain why alcohol can make people feel sleepy and change their brain activity. Other medicines that help GABAA receivers, like some anxiety medications, also cause calming effects, reduce anxiety, relax muscles, and prevent seizures.

GABAB receivers are another type of calming receiver. They are also found in many parts of the brain. For GABAB receivers to work, two main parts need to link up. Alcohol is known to affect GABAB receivers, but how it does this is not fully understood. Medicines that work on GABAB receivers can help with seizures, pain, and have been found to reduce cravings and withdrawal symptoms in people who are dependent on alcohol.

How Alcohol Use Leads to Alcohol Use Disorder (AUD) and Involves GABA

Doctors classify alcohol use problems based on how many symptoms a person has, from mild to severe. These problems are linked to different drinking patterns that affect the brain and the GABA system. Even small amounts of alcohol can change how the GABA system works, leading to changes in behavior. When someone drinks a lot for a long time, or drinks heavily at once (binge drinking), alcohol affects the brain even more, changing other brain chemical pathways.

For example, when someone drinks a little, like one or two drinks a day, it can make GABAA receivers work better, leading to feelings of relaxation. Even in animals, small amounts of alcohol cause less anxiety by affecting these GABA receivers. Over time, even low levels of alcohol can change how GABAA receivers are built and where they are in the brain. These changes can be reversed, but how long it takes to recover depends on how much was drunk.

When someone drinks more, like during "medium-risk" drinking (not quite binge drinking, but more than usual), alcohol levels in the brain can lead to slight sleepiness, feelings of relief, minor memory changes, less attention, and mood changes. In animals, this level of drinking can increase GABA activity in the brain's reward center, which can make them drink more. Studies in animals also showed that reducing certain GABA receiver parts or blocking GABA receivers could reduce alcohol drinking and seeking behaviors, confirming how much GABA helps increase alcohol intake.

Drinking more than recommended is considered "at-risk" drinking. At this level, alcohol activates GABA receivers in many brain areas, leading to more calming effects than exciting ones. At a certain point, the brain's reward pathways are strongly activated, releasing dopamine, which helps alcohol become addictive.

AUD happens when drinking patterns are above healthy limits. One common way to check for AUD is a tool from the World Health Organization. AUD can be broken into binge drinking and heavy drinking. Binge drinking means drinking a lot of alcohol quickly. This can lead to trouble thinking, less control over drinking, and a higher chance of future AUD. Factors like age, being male, starting drinking young, mental health, and genetics can increase the risk. Animal studies show that binge drinking in young animals can cause anxiety and lead to alcohol dependence later in life. In humans, binge drinking can reduce GABA levels in the brain. Studies show that increasing GABA calming effects can help reduce binge drinking.

Heavy drinking means drinking more than the weekly recommended limits. This can cause brain damage and is linked to a higher risk of dependence, anxiety, depression, thinking problems, and other health issues. The changes in behavior from heavy drinking are mainly due to how GABAA receivers change. These changes mean that the brain gets used to alcohol and might not react as strongly to it. This can make people more likely to become dependent. Stress and anxiety can also make heavy drinking worse, and in turn, stopping or reducing alcohol can make stress or anxiety worse due to the brain's imbalance.

With long-term, daily alcohol use, there's a higher risk of always wanting alcohol and not being able to stop. This is often linked to dependence, a serious form of AUD where a person needs alcohol to prevent withdrawal symptoms. Alcohol dependence needs full treatment to help with the body, mind, and behavior aspects.

Studies after death have found fewer GABA-related signs in the brains of adults with alcohol dependence, especially in men. Studies using special brain stimulation also show that long-term alcohol dependence affects GABA receiver function, but this can vary. Some studies found lower overall GABA levels in people with alcohol dependence, including young people. The GABA levels seen can depend on how recently someone stopped drinking and their age.

Many animal studies show that long-term alcohol use changes how GABAA receivers work, leading to alcohol dependence. This results in less overall calming effect from GABA, tolerance to alcohol, and also tolerance to other calming medicines. This means a big imbalance in how excited or calm different brain parts are, leading to behavior changes like trouble thinking, seeking alcohol, and mood swings. During alcohol withdrawal, some GABAA receivers increase while others decrease. This can lead to anxiety and seizures. Also, levels of dopamine and serotonin, which affect mood, drop during withdrawal, leading to feeling down and increasing the desire to drink again.

Current Treatments

Current treatments for AUD and alcohol withdrawal try to use what is known about how alcohol affects the brain. These treatments have different levels of success and can have side effects. Some are approved by health organizations, and others are used in ways not specifically approved but have shown promise.

Non-GABA-Related Medicines: One older approved medicine, disulfiram, makes people feel very sick if they drink alcohol. It stops the body from breaking down alcohol completely, which causes bad side effects. Another common medicine is naltrexone, which reduces cravings by making alcohol less rewarding and enjoyable. It is generally safe and has minor side effects. Acamprosate is another approved medicine used for cravings and preventing return to use It may reduce a brain chemical called glutamate during withdrawal and indirectly helps GABA receivers. Nalmefene also reduces cravings by affecting brain chemicals related to reward and can help control alcohol intake, especially with other support. It usually has mild side effects.

GABA-Related Medicines: Baclofen is approved in some countries for alcohol withdrawal. It works on GABAB receivers and can reduce cravings and withdrawal symptoms, but its overall effectiveness is still debated. It can have many side effects. Gabapentin, used for seizures, has shown promise in reducing cravings and anxiety for AUD, but it can make people sleepy and has been misused. Its exact way of working is not clear, but it increases GABA in the brain. Topiramate, another seizure medicine not yet fully approved for AUD, has shown to reduce cravings and relapse risk. It seems to work by affecting GABAA receivers and also reduces glutamate and dopamine. It can have side effects like tingling, taste changes, and trouble concentrating. Benzodiazepines (BZ) are strong calming medicines that help GABAA receivers work better. They are recommended for severe alcohol withdrawal but not for long-term AUD treatment because they can cause sleepiness, balance problems, memory loss, and can be abused. Drinking alcohol while taking BZ can make effects stronger and increase overdose risk.

Talking Therapies: Cognitive Behavioral Therapy (CBT) is a type of talk therapy that helps people change their thinking and behaviors. It is one of the most studied and supported treatments for substance use problems. People with drinking problems who receive CBT often drink less. Newer versions of CBT, like those using virtual reality, seem to be even more helpful. Motivational Enhancement Therapy (MET) is another talk therapy that helps people find their own reasons to change their drinking habits. It can be very short and focuses on helping people commit to changing.

However, current treatments have limits. Some medicines affect the GABA system directly or indirectly. The GABA system is very important in AUD and withdrawal and is a good target for new medicines. How alcohol affects GABA can vary depending on how a person drinks. This means different treatments that work on different parts of the GABA system might be needed for the best results.

New GABA-Based Treatments in Animal Studies

Since alcohol greatly affects GABA activity and GABA receiver function, it can be hard to know what a GABA-acting medicine will do in people with AUD. Benzodiazepines (BZ), which enhance GABA's calming effect, are helpful for acute withdrawal symptoms because they act as a substitute for alcohol and help the brain regain balance without alcohol.

In recent years, new BZ-like medicines have been made that focus on specific parts of the GABAA receivers. In animal studies, some of these new medicines made alcohol more rewarding, which could be a problem. This fits with studies in people that link certain GABA gene types to a higher risk of alcoholism. Similarly, making another type of GABAA receiver work better also made alcohol more rewarding in animals. However, blocking these receivers reduced the rewarding effects of alcohol. This suggests that these specific GABAA receivers play a role in alcohol-seeking behaviors.

These studies mainly looked at how these medicines affect alcohol use when the brain is already used to alcohol. It's not clear how they would work during withdrawal when the GABA system is not working enough, which causes cravings. But, since BZ can reduce cravings, these new medicines might help with cravings during withdrawal without all the side effects of regular BZ.

Besides BZ, natural substances called neurosteroids also affect GABAA receivers, especially in a way that helps calm the brain's basic activity. With short-term alcohol use, levels of a neurosteroid called allopregnanolone go up. But with long-term alcohol use and withdrawal, its levels go down. Stimulating these neurosteroids has been shown to reduce drug use in animals, suggesting a similar effect for alcohol. Neurosteroids are involved in feelings, thoughts, and motivation, so they might be helpful in treating AUD.

The role of GABAB receivers in AUD is still being explored. However, studies in people and animals show that medicines affecting GABAB receivers can help manage AUD. For example, in animals, a medicine called baclofen reduced over-activity from alcohol and reduced anxiety and tremors during withdrawal. Other new GABAB-affecting medicines are also being studied in animals and have shown positive results for AUD.

New GABA-Based Treatments in Human Studies

With more knowledge about how alcohol affects the GABA system, more human studies are starting to see how GABA-focused treatments can help with AUD and withdrawal. For example, some benzodiazepines are already standard care for reducing withdrawal symptoms. Other related medicines were studied for their effects on stress and immune function in people with AUD.

A neurosteroid medicine called brexanolone, which affects GABAA, is starting a human study to check its safety and how well it works for people with AUD and PTSD. Brexanolone is already approved for treating a type of depression after childbirth.

Baclofen, a GABAB-affecting medicine, is currently in a large study to see how well it works for acute alcohol withdrawal. While it is approved in some places for cravings and withdrawal, some research suggests it may not be that effective. Another medicine, ASP8062, which also affects GABAB, is being studied in humans for its ability to reduce alcohol cravings. Animal studies showed good results without the side effects of baclofen, and early human studies confirmed its safety.

An epilepsy medicine called valproate also indirectly affects the GABA system by increasing GABA levels in the brain. Human studies are ongoing to see if valproate can help reduce alcohol withdrawal symptoms compared to benzodiazepines. Earlier studies showed that valproate combined with another medicine significantly reduced anxiety, depression, and cravings.

Non-Medicine Treatments – Brain Stimulation: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive way to change brain activity using magnetic pulses. It is being studied as a possible treatment for AUD. This treatment can lead to lasting changes in how excited or calm the brain is, which affects GABA activity. Early studies showed it could reduce cravings in adults with AUD. Most studies have focused on specific parts of the brain and have shown promise in reducing cravings. However, many of these studies were small, so more research is needed to find the best way to use this treatment.

There is also growing interest in deeper brain stimulation methods. For example, one recent study using a deeper stimulation showed good results in reducing cravings and drinking in people seeking AUD treatment. Another study showed success for nicotine dependence, leading to approval for that condition. This shows the potential for brain stimulation in treating substance use disorders. It will be important to see if measuring GABA levels can help predict how well rTMS works for AUD.

Conclusion

Alcohol-related problems greatly increase the risk of other serious diseases that can cause death. Although the exact ways alcohol works are not fully known, the GABA system seems to be very important in how AUD develops. Currently, medicines that affect GABA are used as second or third-choice treatments for AUD and to help with alcohol withdrawal. Studies suggest that changing how GABA receptors work through medicines could be a promising way to help people stop drinking long-term by reducing daily alcohol intake and withdrawal symptoms. However, a lot more research is needed to fully discover how the GABA system can be used to treat alcohol-related disorders.